Clinical trial NCT00660673
Conditions: Advanced Parkinson's Disease
Keywords: levodopa/carbidopa intestinal gel Severe Motor Fluctuations Levodopa Carbidopa Parkinson's Disease Dyskinesia
Sponsor: AbbVie
Start date: 2009-11-13; Completion date: 2021-11-30
Enrollment: 262 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to provide continued access to levodopa-carbidopa intestinal gel (LCIG), to participants who have already participated in an open-label efficacy and safety study with the same treatment (Study S187.3.003 \[NCT00360568\] or Study S187.3.004 \[NCT00335153\]).

Detailed description:

Arms: arm 1: Initial dosing is based on the dosing regimen that the participant received during the previous LCIG study. Dosing is individually optimized and can be adjusted at any time during the study as clinically indicated. The total dose/day of LCIG is composed of 3 individually adjusted doses. The morning dose is administered as a bolus infusion, usually 5 to 10 mL (100 to 200 mg levodopa). The maintenance dose is adjustable in steps of 2 mg/hour (0.1 mL/hour), within a range of 1 to 10 mL/hour (20 to 200 mg levodopa/hour) and is usually 2 to 6 mL/hour (40 to 120 mg levodopa/hour). Participants will be allowed to self-administer extra doses of LCIG to address immediate medical needs, normally 0.5 to 2.0 mL.

Participants will receive LCIG until it is commercially available.
Interventions: intervention 1: Levodopa-Carbidopa Intestinal Gel (LCIG) intervention 2: CADD-Legacy® 1400 ambulatory infusion pump intervention 3: Percutaneous Endoscopic Gastrostomy with jejunal extension tube (PEG-J)
Intervention descriptions: intervention 1: LCIG for upper-intestinal infusion is a suspension of levodopa (20 mg/mL) and carbidopa (5 mg/mL) in an aqueous gel that is dispensed in a medication cassette reservoir containing 100 mL of LCIG. intervention 2: Portable infusion pump (CADD-Legacy Pump Model 1400) connected to the LCIG medication cassette reservoir. intervention 3: All participants previously had a PEG-J placed in one of the prior LCIG studies.

Protocol documents:
Prot_000.pdf: 
Levodopa-Carbidopa
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1.0
Title Page
Clinical Study Protocol S187.3.005
Open-Label Continuation Treatment Study with 
Levodopa-Carbidopa Intestinal Gel in Subjects with 
Advanced Parkinson's Disease and Severe
Motor-Fluctuations Who Have Exhibited a Persistent 
and Positive Effect to Treatment in Previous Studies
Incorporating Global Amendments 1, 2 and 3, UK 
Amendment 2, Amendment 3.01 for UK, and Global 
Amendment 4
Investigational Product:
Levodopa-Carbidopa
Date: 
17 December 2013
Development Phase:
3
Study Design:
This is a Phase 3B, open-label, multicenter continuation treatment study.
EudraCT Number:
2008-001329-33
Investigators:
Investigator information on file at AbbVie.
Sponsor:
AbbVie*
Sponsor/Emergency 
Contact:
 MD
Medical Director
Quintiles Medical & Scientific Services
San Diego, CA  92121
Office:
24 hour Urgent Medical 
Contact: +1 973-659-6677 or
+1 570-819-8565 
(alternate number)
 MD
Medical Advisor
Quintiles Medical & Scientific Services
Neurology, CNS, Therapeutic Delivery Unit
Sredniy prospect 36/40 
Letter 'K'
Commerce Center "Gustav" 7 floor
199004 Saint Petersburg
Russia
Office:
24 hour Urgent Medical 
Contact: +1 973-659-6677 or
+1 570-819-8565 
(alternate number)
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
*The specific contact details of the AbbVie or AbbVie's delegated legal/regulatory entity (person) within 
the relevant country are provided within the clinical trial agreement with the Investigator/Institution and in 
the Clinical Trial Application with the Competent Authority.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
 
NCT00660673


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1.1
Protocol Amendment:  Summary of Changes
The purpose of this global amendment is to:
●
Add language to allow for a legally authorized representative (LAR) to give 
informed consent
Rationale:  To allow for a legally authorized representative to provide 
informed consent if a subject does not have the capacity to provide full 
informed consent.
●
Add language regarding transfer of subjects to commercial product
Rationale:  To clarify the assessments that must be performed prior to subjects 
transferring to commercial product.
●
Update clinical device labeling information 
Rationale:  To clarify that storage conditions are not found on the device 
labels.  
●
Update drug and device accountability information 
Rationale:  To clarify the process of drug and device accountability using the 
ClinPhone Drug Accountability (CDA) system.
●
Update language regarding Adverse Events of Special Interest (AESI) 
Rationale:  To clarify the use of questionnaires to collect follow-up 
information for both serious and nonserious AESIs meeting pre-defined 
criteria.
The following changes will apply to US sites only:
●
Add the following assessments:  Parkinson's Disease Symptom Diary, 
UPDRS, PDQ-39, Dosing Diary  
Rationale:  To allow for demonstration of maintenance of efficacy.
This information was updated in the following sections:
●
Section 1.2:  Synopsis
●
Section 3.0:  List of Abbreviations and Definition of Terms


Levodopa-Carbidopa
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●
Section 4.3:  Subject Information and Consent
●
Section 5.0:  Introduction
●
Section 6.0:  Study Objectives
●
Section 7.0:  Study Design
●
Section 8.1:  Inclusion Criteria
●
Section 10.3:  Ordering, Storage and Dispensing of Medication and Device
●
Section 10.9:  Treatment Compliance
●
Section 11.0:  Study Assessments (Criteria for Evaluation) and Flow Chart
●
Section 11.2:  Efficacy Measurements
●
Section 11.3:  Other Assessments
●
Section 11.4:  Appropriateness of Measurements
●
Table 2:  Flow Chart of Study Assessments
●
Section 12.1.4:  Adverse Events of Special Interest
●
Section 13.2:  Analysis Populations
●
Section 13.3:  Statistical Methods 
●
Section 13.5:  Sample Size
An itemized list of changes made to this protocol amendment can be found in 
Appendix B.


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1.2
Synopsis
Name of Sponsor:  AbbVie
Protocol Number:  S187.3.005
Name of Finished Product:  Levodopa-Carbidopa 
Intestinal Gel (LCIG) 20 mg/mL - 5 mg/mL
Phase of Development:  3
Name of Active Ingredient:  Levodopa-Carbidopa
Date of Protocol Synopsis:  17 December 2013
Protocol Title:
Open-Label Continuation Treatment Study with Levodopa-Carbidopa Intestinal Gel in Subjects with 
Advanced Parkinson's Disease and Severe Motor-Fluctuations Who Have Exhibited a Persistent and 
Positive Effect to Treatment in Previous Studies
Study Center(s) (Planned):
Approximately 70
Study Duration:
The protocol duration is planned until the finished product is available commercially in the respective 
countries where subjects are participating in the study.  The expected protocol duration will continue 
through successful NDA and subsequent approval (approximately 4 years).  The protocol duration will 
be extended 4 years in the UK from the approval date of Amendment 3.01.  If it is deemed necessary to 
continue treatment after 4 years in the UK, either an amendment will be made to the current protocol 
or a new protocol will be submitted.
Objectives:
The primary objective is to provide continued access to subjects who would like to continue 
Levodopa-Carbidopa Intestinal Gel (LCIG), after completion of an open-label study (S187.3.003 or 
S187.3.004).
The secondary objectives are to assess the long-term safety and tolerability of the LCIG therapeutic 
system, and to assess the maintenance of efficacy using data collected from US subjects.
Methodology:
This is a Phase 3B, open-label, multi-center, study.  Subjects will be provided with LCIG, if judged 
medically indicated and if it is not commercially available.  Data collected will be for evaluation of safety 
and efficacy, and for periodic assessment of the continued appropriateness of the subject's participation in 
the study.  The decision to continue is based on the Principal Investigator's clinical judgment.
Number of Subjects (Planned):
It is anticipated that approximately 275 subjects who had participated and completed one of the 
open-label LCIG clinical trials will be eligible for this continued treatment with LCIG, until it is 
commercially available.


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Diagnosis and Main Criteria for Inclusion:
In order to be eligible to participate in this study, subjects must meet the following criteria:
1. The subject should have completed participation in Study S187.3.003 or S187.3.004; and, in the 
opinion of the Principal Investigator, would benefit from long-term treatment with LCIG.  For 
Canada, subjects will be allowed to participate in the S187.3.005 study with a minimum of 
6 months of exposure to LCIG in the S187.3.004 study.
2. The subject must be able to understand the nature of the study and must provide written informed 
consent prior to the conduct of any study related procedures.  If the subject does not have the 
capacity to provide informed consent, full informed consent must be obtained from the subject's 
legally authorized representative.  Consenting will be performed according to local regulations.
Main Criteria for Exclusion:
Subjects meeting any of the exclusion criteria listed below at Baseline must be excluded from 
participation in the study. 
1. Medical, laboratory, psychiatric, or surgical issues deemed by the Investigator to be clinically 
significant, and which could interfere with the subject's participation in the study.
Investigational Product, Dose and Mode of Administration:
LCIG is a homogenous suspension of levodopa (20 mg/mL) and carbidopa monohydrate (5 mg/mL) in an 
aqueous intestinal gel (carboxymethylcellulose).  LCIG (levodopa [20 mg/mL] and carbidopa 
monohydrate [5 mg/mL]) is delivered to the proximal small intestine through a jejunal extension tube 
inserted via percutaneous endoscopic gastrostomy (PEG-J).  The intestinal gel is dispensed in a 
medication cassette reservoir of 100 mL, designed to be connected to a portable subject-operated pump.  
LCIG infusion is administered over a full 16-hour period.  The gel will be administered as one morning 
dose, followed by continuous infusion for the remainder of the 16-hour period.  In addition to the 
morning dose and the continuous infusion, subjects will be allowed to self-administer additional doses of 
LCIG to address immediate subjective needs, such as the deterioration of motor function.  It is 
recommended that no more than five extra doses are given per day.  If subjects find it necessary to 
self-administer an increasing number of extra doses (> five/day) of LCIG, they will be instructed to 
contact their physician for appropriate follow-up care (adjustment of continuous infusion) as needed.  At 
night, after disconnecting the pump, the tubing is flushed with potable water.
Duration of Treatment:
In countries where LCIG is not commercially available, the treatment will be made available to subjects 
who complete participation in either LCIG open-label Study S187.3.003 or S187.3.004.  Such product 
will be made available by the Sponsor in accordance with all local regulations as long as such is 
warranted by the therapeutic benefit.  The latter will be determined in consultancy with the responsible 
neurologist, the subject and the Sponsor.  Subjects who continue to receive study drug will be evaluated 
at least semi-annually by the Investigator.  In cooperation with the investigational site, all necessary 
support will be provided by the Sponsor's local representatives.
Reference Therapy, Dose and Mode of Administration:
Not applicable.


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Criteria for Evaluation:
Safety and Tolerability Assessments:
Safety will be assessed by:

Physical examination, including weight

Neurological examination

Vital signs

Resting ECGs

C-SSRS

Clinical laboratory assessments including biochemistry, hematology,  urinalysis, and special labs 
to monitor for vitamin deficiencies

Concomitant medication usage

Adverse event monitoring (including sleep attacks, development of impulsive behavior and of 
melanoma)

Monitoring complications of the infusion device
Tolerability will be assessed by the number of subjects who complete the study.
Efficacy Assessments at US Sites Only:

Parkinson's Disease Diary© assessment of motor state completed for the 3 consecutive days prior 
to each clinic visit

The Unified Parkinson's Disease Rating Scale (UPDRS)

Parkinson's Disease Questionnaire-39 (PDQ-39)
Statistical Methods:
The primary statistical objective of this study will be to evaluate the long-term safety of LCIG.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of study medication in this 
study.
Efficacy Population:
The Efficacy Population includes all subjects at US sites who have taken at least one dose of study 
medication in this study and have at least one efficacy assessment in this study.  
Safety:
The safety population will be used for the analysis of the safety and tolerability data.
Safety will be evaluated using adverse events (AEs), complications of the infusion device, and changes in 
laboratory parameters, electrocardiograms, vital signs, C-SSRS and the Minnesota Impulsive Disorders 
Interview (MIDI).


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Statistical Methods (Continued):
Efficacy:
The Efficacy Population will be used for the analysis of the efficacy data.
The mean change from baseline will be summarized for the following endpoints:

Off time, On time with troublesome dyskinesia, and On time without troublesome dyskinesia as 
measured by the Parkinson's Disease Diary

UPDRS total score, Parts I, II, II and IV scores, and dyskinesia item score

PDQ-39 summary index and domain scores
For the analysis of change from baseline in efficacy measures, each subject's baseline will be their 
baseline measure in the first LCIG study in which they participated (e.g., Study S187.3.001, 
Study S187.3.002 or Study S187.3.004).


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
2.0
Table of Contents.....................................................................8
3.0
List of Abbreviations and Definition of Terms...................12
4.0
Ethics.......................................................................................13
4.1
Independent Ethics Committee or Institutional Review Board ...............13
4.2
Ethical Conduct of the Study ...................................................................14
4.3
Subject Information and Consent.............................................................14
5.0
Introduction ...........................................................................15
6.0
Study Objectives....................................................................19
6.1
Primary Objective ....................................................................................19
6.2
Secondary Objectives...............................................................................19
7.0
Study Design...........................................................................20
7.1
Overall Study Design and Plan Description ............................................20
7.2
Discussion of Study Design, Including the Choice of Control 
Groups......................................................................................................23
8.0
Selection of Study Population...............................................23
8.1
Inclusion Criteria .....................................................................................23
8.2
Exclusion Criteria ....................................................................................23
9.0
Removal of Subjects from Therapy or Assessment ...........24
10.0
Treatments .............................................................................25
10.1
Treatment to be Administered .................................................................25
10.1.1
LCIG ........................................................................................................25
10.1.2
Percutaneous Endoscopic Gastrostomy ...................................................25
10.1.3
Maintenance of LCIG Infusion System ...................................................26
10.1.4
Removal of the PEG-J .............................................................................26
10.2
Packaging and Labeling...........................................................................26
10.3
Ordering, Storage and Dispensing of Medication and Device.................26
10.4
Method of Assigning Subjects to Treatment Groups...............................27
10.5
Selection of Doses in the Study ...............................................................28


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10.6
Selection and Timing of Dose for Each Subject ......................................28
10.6.1
LCIG Infusion..........................................................................................28
10.6.2
Post LCIG Infusion Night-Time Treatment.............................................30
10.6.3
Oral Rescue Medication...........................................................................30
10.7
Blinding and Treatment Code Information ..............................................31
10.8
Prohibited/Concomitant Medication........................................................31
10.9
Treatment Compliance.............................................................................32
11.0
Study Assessments (Criteria for Evaluation) and 
Flow Chart..............................................................................34
11.1
Safety Assessments..................................................................................34
11.1.1
Adverse Events ........................................................................................34
11.1.2
Sleep Attacks ...........................................................................................34
11.1.3
Assessment for Melanoma.......................................................................35
11.1.4
Assessment of Impulsive Behavior..........................................................35
11.1.5
Columbia-Suicide Severity Rating Scale (C-SSRS)................................36
11.1.6
Vital Signs................................................................................................37
11.1.7
Physical Examination...............................................................................37
11.1.8
Neurological Examination .......................................................................37
11.1.9
Laboratory Evaluations............................................................................38
11.1.10
Electrocardiograms ..................................................................................39
11.1.11
PEG-Site ..................................................................................................40
11.1.12
Radiological Check of Tube Placement...................................................40
11.1.13
Complications of the Infusion Device .....................................................40
11.1.14
Yearly Check of PEG Site by Gastroenterologist....................................40
11.2
Efficacy Measurements............................................................................41
11.2.1
Parkinson's Disease Diary (Symptom Diary) ..........................................41
11.2.2
UPDRS.....................................................................................................41
11.2.3
PDQ-39 ....................................................................................................43
11.3
Other Assessments ...................................................................................44
11.4
Appropriateness of Measurements...........................................................45
11.5
Primary Outcome Measure ......................................................................45
11.6
Flow Chart of Study Assessments ...........................................................45
12.0
Adverse Events.......................................................................48


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12.1
Adverse Events and Adverse Drug Reactions .........................................48
12.1.1
Recording of Adverse Events ..................................................................50
12.1.2
Follow-Up of Adverse Events .................................................................53
12.1.3
Follow-Up of Product Quality Complaints..............................................53
12.1.4
Adverse Events of Special Interest ..........................................................53
12.2
Serious Adverse Events (SAEs) and Serious Adverse Drug 
Reactions (SADRs)..................................................................................54
12.2.1
Reporting Serious Adverse Events ..........................................................55
12.2.2
Reporting of Serious Adverse Drug Reactions and Suspected 
Unexpected Serious Adverse Drug Reactions to Regulatory 
Authorities and Investigators ...................................................................57
12.3
Pregnancies ..............................................................................................58
13.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................58
13.1
Statistical Objective .................................................................................58
13.2
Analysis Populations................................................................................59
13.3
Statistical Methods...................................................................................59
13.4
Alpha Level Tested ..................................................................................61
13.5
Sample Size..............................................................................................61
14.0
Investigator Obligations........................................................61
14.1
Essential Documents................................................................................62
14.2
Electronic Case Report (eCRF) Form Completion..................................62
14.3
Essential Records Retention ....................................................................63
14.4
Investigator Agreement............................................................................64
14.4.1
Investigator's Agreement/Signature .........................................................65
15.0
Sponsor Obligations ..............................................................66
15.1
Protocol Amendments..............................................................................66
15.2
Study Monitoring .....................................................................................67
15.3
Quality Assurance Audits ........................................................................67
15.4
Annual Reporting.....................................................................................68
16.0
Publication Policy..................................................................68
17.0
Insurance................................................................................68
18.0
References...............................................................................69


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List of Tables
Table 1.
Laboratory Evaluations............................................................................39
Table 2.
Flow Chart of Study Assessments ...........................................................46
List of Figures
Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System..............................18
List of Appendices
Appendix A.
List of Protocol Signatories......................................................................71
Appendix B.
Protocol Amendment:  List of Changes...................................................72


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3.0
List of Abbreviations and Definition of Terms
ADR
Adverse drug reaction
AE
Adverse event
β-HCG
Beta-human chorionic gonadotropin
CDA
ClinPhone Drug Accountability
COMT
Catechol-O-methyltransferase 
C-SSRS
Columbia-Suicide Severity Rating Scale
DBS
Deep brain stimulation
EDC
Electronic data capture
EudraCT
European clinical trials database
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
IB
Investigator's Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
LCIG
Levodopa-Carbidopa Intestinal Gel
ND
Nasoduodenal
NDA
New Drug Application
MIDI
Minnesota Impulsive Disorders Interview 
PD
Parkinson's disease
PDQ-39
Parkinson's Disease Questionnaire
PEG-J
Percutaneous endoscopic gastrostomy – with jejunal extension tube
PSUR
Periodic Safety Update Report
SADR
Serious adverse drug reaction
SAE
Serious adverse event
SUSAR
Suspected unexpected serious adverse drug reaction
UPDRS
Unified Parkinson's Disease Rating Scale


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4.0
Ethics
4.1
Independent Ethics Committee or Institutional Review 
Board
The Sponsor (or an authorized representative) or the Investigator (according to national 
provisions) is responsible for obtaining written approval for the clinical study protocol 
(including all substantial protocol amendments), the written subject informed consent 
form (including written assent, when applicable), informed consent updates, subject 
recruitment procedures (e.g., advertisements) and any other written information to be 
provided to subjects from an Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) that complies with the local regulatory requirements.
Written approval of the study must be obtained from the IEC/IRB prior to the study being 
implemented (i.e., shipment of clinical supplies to the Investigator or screening of 
subjects).  Copies of the approval documentation will be maintained by both the 
Investigator and the Sponsor (or an authorized representative) in the designated study 
files.
The Sponsor (or an authorized representative) or the Investigator (according to national 
provisions) will submit written reports of the clinical study status to the IEC/IRB 
annually, or more frequently if requested by the IEC/IRB.  A final study notification 
should be forwarded to the IEC/IRB within 90 days after the study has completed, or in 
the event of early termination of the study, within 15 days with the rationale for study 
termination clearly explained.  Copies of all clinical study status reports (including 
termination) will be maintained by both the Investigator and the Sponsor (or an authorized 
representative) in the study documentation files.
In accordance with national provisions and the rules of the European Union (EU) Clinical 
Trial Directive, the Sponsor (or an authorized representative) will inform all participating 
IECs/IRBs and national authorities of all serious adverse events (SAEs)/serious adverse 


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drug reactions (SADRs)/suspected unexpected serious adverse drug reaction (SUSARs) or 
other safety related information that occur during the clinical study.
4.2
Ethical Conduct of the Study
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting studies that involve the participation of 
human subjects.  The study will be conducted in compliance with GCP and the applicable 
national regulations so as to assure that the rights, safety and well being of the 
participating study subjects are protected consistent with the ethical principles that have 
their origin in the Declaration of Helsinki.
4.3
Subject Information and Consent
Voluntary written informed consent will be obtained from each subject prior to 
performing any study-related procedures.  Each subject will be given both verbal and 
written information describing the nature and duration of the clinical study.  The informed 
consent process will take place under conditions where the subject has adequate time to 
consider the risks and benefits associated with his/her participation in the study.  Subjects 
will not be screened or treated until the subject has signed an IEC/IRB approved informed 
consent written in a language that is understandable to the subject.
The IEC/IRB approved informed consent form will be signed and personally dated by the 
subject (and if appropriate, their caregiver) and the person who conducted the informed 
consent discussion.  If the subject does not have the capacity to provide informed consent, 
full informed consent must be obtained from the subject's legally authorized 
representative.  Consenting will be performed according to local regulations.  Each 
subject is to receive a copy of the signed and dated written informed consent form and any 
other written subject information.
The Investigator is responsible for assuring the appropriate content of the informed 
consent form and that informed consent is obtained from each subject in accordance with 


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the applicable regulations and guidelines.  The original signed informed consent is to be 
retained in the study documentation files at the study site.
The Investigator shall maintain a log of all subjects who sign the informed consent form 
and indicate if the subject received study drug or, if not, the reason why.  The subject's 
medical records should also document that the informed consent form was signed and 
dated prior to any study-related procedures being performed.
5.0
Introduction
The combination of levodopa/carbidopa continues to be a mainstay in the treatment of 
Parkinson's disease (PD).1-4  Levodopa relieves symptoms of PD following 
decarboxylation to dopamine in the brain.  Carbidopa, which does not cross the blood 
brain barrier, inhibits the extracerebral decarboxylation of levodopa, which means that a 
larger amount of levodopa becomes available for transportation to the brain and 
transformation into dopamine.  Without the simultaneous administration of carbidopa, 
much larger amounts of levodopa would be required to achieve the desired effect.
In advanced stages of PD, patients treated with oral levodopa may develop severe motor 
fluctuations characterized by unpredictable swings from mobility to immobility ("on-off" 
phenomenon) leading to significant difficulties in disease management.  Patients with 
advanced PD continue to experience significant symptoms despite an increase in the dose 
or frequency of oral administration of levodopa; likely, this is a combined result of the 
short half-life of levodopa and the unpredictable variability of gastric emptying.  Patients 
can also experience troublesome involuntary movements or dyskinesias during "On" 
periods so that they cycle between on periods with dyskinesia and "Off" periods with 
Parkinsonism.5  Accordingly, patients with advanced disease suffer severe disability 
despite current levodopa treatment.  However, there is increasing evidence that continuous 
infusion of levodopa can reduce both off time and dyskinesia.1,6
The motor fluctuations and dyskinesias after oral intake of levodopa may be explained by 
an underlying progression of the disease with gradual disappearance of dopaminergic 


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neurons in the brain.  When approaching a certain threshold of degeneration of 
dopaminergic and other neurons, an individuals' capacity to store dopamine in the brain 
and ability to respond to levodopa becomes increasingly unstable.  It has been 
hypothesized that the therapeutic plasma levodopa concentration window becomes 
increasingly narrow over time.  As a result there is an insufficient response 
(Parkinsonism) when the levodopa concentration is below the window, and troublesome 
dyskinesias occur when the concentration increases above an upper threshold for the 
individual.  The incidence of motor fluctuations and dyskinesias among patients treated 
with oral levodopa/carbidopa varies between 20% and 50% of the patients in different 
studies.3,4
Various approaches have been taken to cope with the increasingly unstable levodopa 
response.  Manipulations of levodopa dose are typically not effective.  Dopamine agonists 
may be of some value, but are not adequate in advanced cases.  Oral formulations of 
levodopa are often prescribed in combination with long-acting dopamine agonists and 
catechol-O-methyltransferase (COMT) inhibitors.7  However, despite individually 
optimizing treatment with these conventional medications, patients with advanced PD 
often do not experience adequate control of their motor performance.  Therefore, 
additional treatment strategies are needed for these patients.  A number of approaches 
have been explored and utilized with varying degrees of success; they include the 
continuous intravenous (IV) administration of levodopa1,8-10 and deep brain stimulation 
(DBS).11  Due to issues of technical and logistic feasibility, continuous administration of 
intravenous (IV) levodopa has not received wide application.  DBS has been used in the 
treatment of advanced PD patients and has demonstrated improvement of motor 
fluctuations in this patient population, but severe complications have been reported in a 
substantial number of patients; the procedure is not available in all settings, it is 
expensive, and not all PD patients are candidates for brain surgery.12
Almost three decades ago, it was clearly demonstrated that constant-rate delivery 
(infusion) of levodopa to the blood markedly stabilized motor performance in advanced 
PD patients.9,10,13


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LCIG is a suspension of levodopa:carbidopa (4:1) in an aqueous gel 
(carboxymethylcellulose) with a viscosity that permits homogeneous distribution of 
micronized substance particles.  On upper-intestinal administration, the compounds are 
dissolved in situ and levodopa is rapidly absorbed by an active carrier mechanism 
localized in the proximal small intestine.  LCIG provides continuous rather than 
intermittent stimulation of the dopaminergic receptors in the brain by permitting plasma 
concentrations of levodopa to be kept within the individual's therapeutic window.  When 
delivered via continuous intestinal infusion therapy, LCIG reduces the motor fluctuations 
and increases the "On"-time for patients with advanced PD who have received oral tablet 
treatment with levodopa/decarboxylase inhibitor for many years.  The motor fluctuations 
and hyper-/dyskinesias are reduced when plasma concentrations of levodopa are kept 
within the individual therapeutic window.  Therapeutic effects on motor fluctuations and 
hyper-/dyskinesias are often achieved during the first treatment day.
The delivery of LCIG directly to the proximal small intestine is anticipated to result in the 
following:1,2,13,14
●
Continuous delivery of levodopa-carbidopa
●
Avoidance of the effects of pulsatile gastric emptying
●
Reduced variability in plasma-levodopa concentrations
●
Decreased motor fluctuations and dyskinesias
LCIG is delivered to the proximal small intestine through a catheter inserted via 
percutaneous endoscopic gastrostomy – with jejunal extension tube (PEG-J).  The LCIG 
is dispensed in medication cassette reservoirs.  The contents of the medication cassette 
reservoir are delivered via continuous administration as illustrated in Figure 1.


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Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System
The principle aim of LCIG treatment is to continuously infuse levodopa and carbidopa 
directly into the proximal small intestine (the duodenum and/or jejunum), where it is 
absorbed by a carrier-mediated mechanism.  Absorption problems related to erratic gastric
emptying, early metabolism, and competitive inhibition of intestinal absorption by large 
neutral amino acids will be markedly reduced allowing levodopa to be rapidly absorbed 
into the bloodstream.  It has been demonstrated that an upper-intestinal infusion of 
levodopa is associated with reduced variability in plasma levodopa concentrations as 
compared to oral formulations of levodopa/carbidopa.13
The efficacy of upper-intestinal administration of levodopa has been demonstrated in 
clinical investigations by decreasing motor fluctuations compared to standard oral 
therapy.  Results of a 3-week open-label cross-over study (NPP-001-02), with blinded 
assessments of efficacy, demonstrated clinical and statistical superiority of LCIG 
compared to standard oral therapy with regard to motor fluctuations.2,15  Patients also 
reported significantly improved scores in two Quality of Life (QoL) instruments, the 
Parkinson's Disease Questionnaire (PDQ-39) and EuroQol Quality of Life Scale 
(EQ-5D).2
This open-label, multi-center, Phase 3B study will provide continued treatment with 
LCIG to subjects who have already participated in an open-label treatment study with the 
same treatment (S187.3.003 or S187.3.004).  In countries where LCIG is not yet available 


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commercially, the treatment will be made available by the Sponsor in accordance with all 
local regulations as long as such is warranted by the therapeutic benefit.  The latter will be 
determined in consultancy with the responsible neurologist, the subject and the Sponsor.  
Subjects who continue to receive study drug will be evaluated at least semi-annually by 
the Investigator.  In cooperation with the investigational site, all necessary support will be 
provided by the Sponsor's local representatives.  Additionally, the study will allow for 
observation of the long-term safety, tolerability, and maintenance of efficacy of LCIG 
administered for several years in a more naturalistic treatment environment.
6.0
Study Objectives
6.1
Primary Objective
The primary objective of this study is to provide, under well-controlled conditions, 
continued access to LCIG treatment to subjects who have already participated in an 
open-label efficacy and safety trial with the same treatment (Study S187.3.003 or 
S187.3.004), and in whom the need for such continuation is indicated, as confirmed by 
periodic evaluation, until the product is commercially available.
6.2
Secondary Objectives
To assess the long-term safety and tolerability of the LCIG therapeutic system, and to 
assess the maintenance of efficacy using data collected from US subjects.
Safety and tolerability will be assessed by the following:
●
Physical examination, including weight
●
Neurological examination
●
Vital signs
●
Resting ECGs
●
Columbia Suicide-Severity Rating Scale (C-SSRS)
●
Clinical laboratory assessments including biochemistry, hematology, 
urinalysis, and special labs to monitor for vitamin deficiencies


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●
Concomitant medication usage
●
Adverse event monitoring, including for the development of sleep attacks,  
melanoma, or excessive impulsive behavior
●
Monitoring complications of the infusion device
●
Tolerability assessed by number of subjects who complete the study
Maintenance of efficacy will be assessed by evaluating the mean change from baseline in 
the following:
●
Off time, On time with troublesome dyskinesia and On time without 
troublesome dyskinesia as measured by the Parkinson's Disease Diary
●
UPDRS total score, Parts I, II, III and IV scores, and dyskinesia item score
●
PDQ-39 summary index and domain scores
For the analysis of change from baseline in efficacy measures, each subject's baseline will 
be their baseline measure in the first LCIG study in which they participated 
(e.g., Study S187.3.001, S187.3.002 or S187.3.004).
7.0
Study Design
7.1
Overall Study Design and Plan Description
This is a Phase 3B, open-label, multi-center study of the long-term safety and tolerability 
of LCIG in the continuation of treatment of approximately 275 advanced Parkinson's 
disease subjects with a good therapeutic response on LCIG with regard to the treatment of 
persistent severe motor fluctuations.  The study will be conducted at approximately 
70 centers.  In addition, maintenance of efficacy will be evaluated at approximately 28 US 
sites.
Only subjects who have completed Study S187.3.003 or S187.3.004 will qualify for 
enrollment in this study.  Following informed consent, subjects will have their 
inclusion/exclusion criteria assessed prior to beginning treatment in this study.  Subjects 
are allowed to have a caregiver, if appropriate, assist them with study requirements, 


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i.e., care of the pump and tubing, etc. and the caregiver will have been trained 
accordingly.
The initial LCIG dose will be identical to the dose that the subject was receiving at the 
end of the previous open-label LCIG study.  Subsequent dose adjustments will be made as 
clinically indicated by the Investigator.
In this open-label study, a recommendation will be made to Investigators to withhold 
concomitant PD treatments if deemed medically safe and clinically appropriate.  The 
initiation of additional PD medication may be medically indicated and is allowed at the 
discretion of the Investigator.  Also, the dosages of these other PD medications can be 
adjusted upward or downward as needed based on the status of the subject's condition or 
the development of adverse effects; resumption of discontinued PD medications may also 
be necessary.
In addition to the morning dose and the continuous infusion, subjects will be allowed to 
self-administer additional doses of LCIG to address immediate subjective needs, such as 
the deterioration of motor function.  If subjects find it necessary to self-administer an 
increasing number of extra doses (> five/day) of LCIG, they will be instructed to contact 
the Investigator for appropriate follow-up care (adjustment of continuous infusion) as 
needed. 
Subject visit days should ideally match the target clinic visit days; however, a 14-day visit 
window will be allowed as necessary.  Attempt should be made to bring the subject back 
on the target visit day.
The final visit in the previous open-label LCIG study will provide baseline assessments 
for the S1878.3.005 study.  Subjects will be reassessed every 6 months for the 
appropriateness of the continuation of treatment with LCIG.  If the subject is deemed 
inappropriate for continued treatment by the Investigator, the subject would be 
discontinued from treatment and the PEG-J will be removed, with a follow-up visit 


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occurring 1 week later.  For subjects who elect not to continue LCIG treatment, the PEG-J 
will be removed, and a follow-up clinic visit will occur 1 week later.
Safety assessments should include physical examination, neurological exam, orthostatic 
vital signs, weight, adverse event monitoring, assessment of impulsive behavior and sleep 
attacks, melanoma check, electrocardiogram (ECG), clinical hematology, biochemistry, 
special labs to monitor for vitamin deficiencies, and urinalysis.
The following efficacy assessments will be completed at US sites: 
●
Parkinson's Disease Diary© assessment of motor state completed for the 
3 consecutive days prior to each clinic visit (excluding the drug dispensation 
visits),
●
Unified Parkinson's Disease Rating Scale (UPDRS), and 
●
Parkinson's Disease Questionnaire-39 (PDQ-39).
At each visit, complications or adverse events with the infusion device (i.e., the tubing 
system and the pump) will also be recorded and reported.  Tube placement will be 
checked by radiography if there is a clinical indication that the tube has been displaced.  
The tube will be repositioned, if needed, to the original placement site just beyond the 
ligament of Treitz.  At each visit the tube insertion site, including the stoma, will also be 
inspected.  On a yearly basis, at a minimum, an assessment will be made of the need for a 
replacement of the PEG-J.  The frequency of replacement should be in accordance with 
local practice.
The protocol duration is planned until the finished product is available commercially in 
the respective countries where subjects are participating in the study.  The expected 
protocol duration will continue through successful NDA and subsequent approval 
(approximately 4 years).  The protocol duration will be extended 4 years in the UK from 
the approval date of Amendment 3.01.  If it is deemed necessary to continue treatment 
after 4 years in the UK, either an amendment to the current protocol will be made or a 
new protocol will be submitted.


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7.2
Discussion of Study Design, Including the Choice of Control 
Groups
This study is an open-label continuation treatment study and all subjects will receive 
open-label LCIG therapy.  In order to be enrolled in this study subjects will need to 
complete Study S187.3.003 or S187.3.004.
8.0
Selection of Study Population
8.1
Inclusion Criteria
In order to be eligible to participate in this study, subjects must meet the following 
criteria:
1.
The subject should have completed participation in Study S187.3.003 or 
S187.3.004; and, in the opinion of the Principal Investigator, would benefit from 
long-term treatment with LCIG.  For Canada, subjects will be allowed to 
participate in the S187.3.005 study with a minimum of 6 months of exposure to 
LCIG in the S187.3.004 study.
2.
The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study related procedures.  If 
the subject does not have the capacity to provide informed consent, full informed 
consent must be obtained from the subject's legally authorized representative.  
Consenting will be performed according to local regulations.
8.2
Exclusion Criteria
Subjects meeting any of the exclusion criteria listed below at Baseline must be excluded 
from participation in the study.
1.
Medical, laboratory, psychiatric, or surgical issues deemed by the Investigator to be 
clinically significant and which could interfere with the subject's participation in 
the study.


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9.0
Removal of Subjects from Therapy or Assessment
All subjects are free to withdraw from participation in the study at any time, for any 
reason, specified or unspecified, and without penalty or loss of benefits to which the 
subject is otherwise entitled.
The Study Termination eCRF must be completed for all subjects who have entered the 
study (i.e., have signed informed consent form), including those subjects who drop out 
prior to study drug administration.
In case of early termination of the subject from the study, the primary reason for this early 
termination is to be indicated according to the following definitions:
●
Adverse event:  Discontinuation due to any AE with a corresponding entry 
reflected on the Adverse Events eCRF.
●
Lack of efficacy:  Subject fails to continue to respond to the study drug at an 
acceptable level, where the subject or the Investigator feels it is in the best 
interest of the subject to seek another treatment.
●
Lost to follow-up:  The subject fails to return for scheduled visits and does not 
respond to telephone or written attempts to contact.
●
Withdrew consent:  Subject decides to stop his/her participation in the study 
for any reason other than an AE, or is unable to complete the study as 
described in the clinical study protocol (e.g., subject is relocating).
●
Administrative:  The Sponsor decides to terminate an individual subject or 
decides to discontinue the study (either at the study site or the entire study),
(e.g., general safety problems leading the Sponsor to stop the study entirely).
●
Protocol violation:  Anything which is in direct violation of the protocol 
(e.g., inclusion/exclusion violation).  All protocol violations are to be 
discussed with the Sponsor prior to the subject being discontinued from the 
study, or as soon as possible in case urgent safety reasons prohibit such 
discussion.


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10.0
Treatments
Study drug and devices will only be shipped to Investigators who have provided the 
Sponsor (or an authorized representative) with all required documents, including IEC/IRB 
approval, and have signed a Clinical Trial Agreement.
10.1
Treatment to be Administered
Subjects will self-administer Levodopa Carbidopa Intestinal Gel (LCIG).  In countries 
where LCIG is not yet available commercially, the treatment will be made available by 
the Sponsor in accordance with all local regulations as long as such is warranted by the 
therapeutic benefit.
The chemical nomenclature for levodopa is (-)-3-(3,4-dihydroxyphenyl)-L-alanine.  The 
chemical name for carbidopa is (-)-L-α-hydrazino-3,4-dihydroxy-α-methylhydrocinnamic 
acid monohydrate.  LCIG for upper-intestinal infusion is a suspension of 
levodopa:carbidopa in an aqueous gel (carboxymethylcellulose).
10.1.1
LCIG
LCIG is supplied as a homogeneous suspension of levodopa (20 mg/mL) and carbidopa 
(5 mg/mL) in an aqueous intestinal gel (carboxymethycellulose).  The intestinal gel is 
dispensed in a medication cassette reservoir of 100 mL, designed to be connected to a 
portable subject-operated pump.  LCIG is administered over approximately 16 waking 
hours.  At night, after disconnecting the pump for sleeping, the tubing is flushed with 
potable water.
The total daily dose of infusion will be composed of three components:  the morning dose, 
the continuous maintenance infusion dose, and extra doses given as needed.
10.1.2
Percutaneous Endoscopic Gastrostomy
The gastric port of the PEG-J is not to be used for the delivery of nutrition and/or other 
medications unless judged medically necessary following consultation with the Medical 


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Monitor.  If the tube must be used for nutrition and/or other medications, it is imperative 
that they are delivered only through the gastric port and not the jejunal port.  The gastric 
port must be properly flushed and maintained if it is used for this purpose.
There may be a need to replace the PEG-J tube during the study.  The frequency of 
change will depend on the condition of the tube and local clinical practice.
10.1.3
Maintenance of LCIG Infusion System
Refer to the Study Reference Manual for a detailed description of the care and 
maintenance of the pump, the PEG-J, and the stoma site.
10.1.4
Removal of the PEG-J
Institutional standards for follow-up care after removal of the PEG-J should be followed.  
To remove the tube, the tube should be cut at skin-level.  The internal disc and the 
remaining tube must be retrieved by endoscope.
10.2
Packaging and Labeling
The medication will be packaged in accordance with the applicable local and federal 
regulations and Good Manufacturing Practices (GMP).
The medication cassette reservoirs of LCIG and the box containing seven (7) medication 
cassette reservoirs will be labeled with all information as required by local regulations.  
All labels must remain affixed to the primary and secondary packaging material.
10.3
Ordering, Storage and Dispensing of Medication and Device
All clinical drug supplies are to be stored at each investigational site in a secure, 
limited-access area according to the label storage conditions.  The Investigator or 
pharmacist/designee will maintain accurate records of the receipt and disposition of all 
clinical medication supplies received during the study.  These records shall include the 
amounts of drug supplies and the dates on which drug supplies were received from the 
Sponsor (or an authorized representative), dispensed to the subject, returned by the subject 


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and returned to the Sponsor (or an authorized representative).  If errors or damages in the 
clinical drug supply shipments occur, the Investigator or pharmacist/designee must 
contact the Sponsor (or an authorized representative) immediately.
All clinical devices (e.g., pumps and tubing) are to be stored in a secure, limited-access 
area.  The Investigator will maintain accurate records of the receipt and disposition of all 
clinical device supplies received during the study.  These records shall include the number 
of clinical devices and the dates on which devices were received from the Sponsor (or an 
authorized representative), dispensed to the subject, returned by the subject and returned 
to the Sponsor (or an authorized representative).  If errors or damages in the clinical 
device shipments occur, the Investigator must contact the Sponsor (or an authorized 
representative) immediately.
Subjects will receive study medication at the Baseline visits, and regular 6 month clinical 
visits.  In addition, subjects do need to come into the clinic or pharmacy for clinical 
supply visits every 6 weeks (± 7 days), so that there is no risk of medication expiring.  
Other assessments may be completed during these visits if required.  When scheduling the 
6 weekly drug dispensing visits, the site should always refer back to the baseline visit.  
Every attempt should be made to bring the subject back on the original targeted dates 
(±7 days).
At the distribution depots, the cassettes with the suspension can be stored in the freezer 
(between –15°C and –25°C) for up to 2 years.  After thawing, the suspension can be 
stored in a refrigerator (between 2°C and 8°C) for up to 15 weeks.  Thawed LCIG 
suspension should not be refrozen.  All study medication should be used within 16 hours 
after removal from the refrigerator.
10.4
Method of Assigning Subjects to Treatment Groups 
All subjects will receive LCIG.


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10.5
Selection of Doses in the Study
Subject dosing will be individually optimized.  The LCIG infusion is expected to infuse 
over 16 hours with a rate of infusion within the range of 1 to 10 mL/hour (20 to 200 mg of 
levodopa/hour) in most instances.
10.6
Selection and Timing of Dose for Each Subject
Initial subject dosing will be based on the dosing regimen that the subject received during 
the previous open-label LCIG study.
The timing (time of day, interval) of dosing and specific instructions to subjects about 
when or how to take the dose(s) are described below.  No restrictions are given with 
relation to the time of dosing relative to meals.
10.6.1
LCIG Infusion
The total dose/day of LCIG is composed of three individually adjusted doses:  the 
morning dose, the continuous maintenance dose and extra doses 
The infusion dose will continue to be individually optimized for each subject during the 
study, by the Investigator, based on response and potential adverse events.  The rate of 
infusion is expected to be within the range of 1 to 10 mL/hour (20 to 200 mg of 
levodopa/hour) in most instances.  The infusion will run over approximately 16 hours.  
The PEG-J is to be disconnected from the infusion pump at bedtime.  Extra doses of 
LCIG can be used to help control fluctuations in the subject's PD symptoms.
Morning Dose:
The morning dose is administered as a bolus infusion by the pump to fill the dead space of 
the intestinal tube and rapidly achieve the therapeutic dose level (within 10 to 
30 minutes).  The total morning dose is usually 5 to 10 mL, corresponding to 100 to 
200 mg levodopa.


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The total morning dose will usually not exceed 15 mL (300 mg levodopa).  However, 
there may be some exceptions to these recommendations based on the Investigator's 
clinical judgment.
Continuous Maintenance Dose:
The maintenance dose is adjustable in steps of 2 mg/hour (0.1 mL/hour).  When 
supplementary medicines are discontinued or added to the treatment regimen, the LCIG 
dose should be adjusted.  The continuous maintenance dose is adjusted individually.  It 
should be kept within a range of 1 to 10 mL/hour (20 to 200 mg levodopa/hour) and is 
usually 2 to 6 mL/hour (40 to 120 mg levodopa/hour).  In exceptional cases, a higher dose 
may be needed based on the Investigator's clinical judgment.
Example:
Daily intake of levodopa as LCIG:  1640 mg/day
Morning dose: 140 mg = 7 mL
Continuous maintenance dose thereafter:  1500 mg/day
1500 mg/day at 20 mg/mL = 75 mL LCIG per day
The intake is calculated over 16 hours:  75 mL/16 hours = 4.7 mL/hour.
Extra Infusion Doses:
Subjects will be allowed to self-administer extra doses of LCIG to address immediate 
medical needs, such as the rapid deterioration of motor function.  Extra doses may be 
given as required if the subject becomes hypokinetic during the day.  The extra dose 
should be adjusted individually, normally 0.5 to 2.0 mL.  In rare cases, a higher dose may 
be needed.  If the need for extra doses exceeds five per day, consideration should be given 
to increasing the maintenance dose.  Additionally, fine adjustments of the morning dose, 
the maintenance dose and extra doses can be made as needed.
During treatment, Investigator consideration should be given to instances in which 
deterioration of treatment response occurs.  In the absence of pump alarm notifications, a 
sudden deterioration in treatment response with recurring motor fluctuations could be the 


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result of the distal part of the tube becoming displaced from the upper intestine into the 
stomach.  The location of the tube should be determined radiographically.  If necessary, 
the end of the tube can be repositioned to the proximal small intestine and the new 
placement confirmed radiographically.
The tube insertion site, including the stoma, should be inspected at each Study Visit.
10.6.2
Post LCIG Infusion Night-Time Treatment
Following the discontinuation of the 16-hour LCIG infusion, subjects will be permitted to 
self administer their typical night-time regimen of levodopa-carbidopa tablets (typical 
evening and night-time doses of oral levodopa-carbidopa that they take on a regular 
basis).   
10.6.3
Oral Rescue Medication
Oral levodopa-carbidopa medication may only be used to supplement treatment at night 
and should NOT be used during the day, except as rescue medication in case of acute 
deterioration presumably caused by failure of the LCIG system such as tubes and/or the 
pump or the onset of an acute illness.  Extra doses of LCIG should be utilized for these 
symptoms during the LCIG infusion.
Subjects should have a supply of oral levodopa-carbidopa IR if for some reason they are 
unable to administer their LCIG infusion.
Oral doses of levodopa-carbidopa taken after the discontinuation of daily LCIG infusion 
(typical evening and night-time doses of oral levodopa-carbidopa taken on a regular basis) 
will not be counted as rescue medication, as long as the number of tablets taken during 
that period does not exceed what the subject routinely takes during those hours.  If the 
subject requires additional oral doses beyond the routine number of tablets of 
levodopa-carbidopa that are needed as part of the subject's typical night-time regimen, 
these additional oral doses should be considered rescue doses.


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10.7
Blinding and Treatment Code Information
Not applicable.  The study has only one treatment arm.
10.8
Prohibited/Concomitant Medication
Concomitant administration of non-selective MAO inhibitors is not permitted.  
Furthermore, concomitant administration of selective MAO type A inhibitors is not 
permitted.
Caution is needed in concomitant administration of LCIG with the following medicinal 
products:
Antihypertensives
Symptomatic postural hypotension has occurred when combinations of levodopa and a 
decarboxylase inhibitor are added to the treatment of subjects already receiving 
antihypertensives.  Dosage adjustment of the antihypertensive agent may be required.
Antidepressants
There have been rare reports of adverse reactions, including hypertension and dyskinesia, 
resulting from the concomitant administration of tricyclic antidepressants and 
carbidopa/levodopa preparations. 
Anticholinergics
Anticholinergics may act synergistically with levodopa to decrease tremor.  However, 
combined use may exacerbate abnormal involuntary movements.  Anticholinergics may 
decrease the effects of levodopa by delaying its absorption.  An adjustment of the dose of 
LCIG may be needed.


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COMT Inhibitors (tolcapone, entacapone)
Concomitant use of COMT (Catechol-O-Methyl Transferase) inhibitors and LCIG can 
increase the bioavailability of levodopa.  The dose of LCIG may need adjustment.
Other Medicinal Products
Dopamine receptor antagonists (some antipsychotics, e.g., phenothiazines, butyrophenons 
and risperidone and antiemetics, e.g., metoclopramide), benzodiazepines, isoniazide, 
phenytoin and papaverine can reduce the therapeutic effect of levodopa.  Subjects taking 
these medicinal products together with LCIG should be observed carefully for loss of 
therapeutic response.
LCIG can be taken concomitantly with the recommended dose of a selective MAO type B 
inhibitor (for instance selegiline-HCl).  However, concomitant use of selegiline and 
levodopa-carbidopa has been associated with serious orthostatic hypotension.
Amantadine has synergic effect with levodopa and may increase levodopa related adverse 
events.  An adjustment of the dose of LCIG may be needed.
Sympathicomimetics may increase cardiovascular adverse events related to levodopa.
Levodopa forms a chelate with iron in the gastrointestinal tract leading to reduced 
absorption of levodopa.
10.9
Treatment Compliance
The Investigator (or designee) must document the amount of study drug dispensed to the 
subject and returned from the subject in the ClinPhone Drug Accountability (CDA) 
System and on the eCRF.  In case of discrepancies in the actual amount of study drug 
returned versus what should have been returned, the subject will provide the Investigator 
(or designee) with an explanation, and the explanation must be recorded in the CDA 
system and in the source notes.


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Drug Accountability
The Investigator (or designee) is accountable for all clinical drug supplies shipped to 
his/her study site for the duration of the study.  Previously completed paper drug 
accountability logs will not be completed anymore, but need to be kept on-site in the 
investigator site file for further reference.  An overall accountability of the study drug will 
be performed and verified by the site and designated monitor throughout the study and at 
the site close-out visit.  After verification of drug accountability using the CDA system, 
all clinical drug supplies must be inventoried, accounted for and returned to the drug 
destruction depot.  A final accounting of the clinical drug supplies will be required at the 
completion/termination of the study.  The Investigator (or designee) is required to provide 
written explanation for any discrepancies.  All used and unused clinical drug supplies will 
be inventoried and returned to the Sponsor (or an authorized representative) by the site or 
by a designated monitor.
Device Accountability
The Investigator (or designee) is accountable for all investigative devices (e.g., pumps, 
tubing) that were shipped to his/her site for use in the study (ancillary supplies).  
Previously completed paper accountability logs for ancillary supplies will not be 
completed anymore, but need to be kept on-site in the investigator site file for further 
reference.  An overall accountability of the ancillary supplies will be performed and 
verified by the site and monitor throughout the study and at the site close-out visit.  After 
verification of device accountability using the CDA system, used or expired unused 
devices, with the exclusion of pumps, will be discarded per the site's institutional policy, 
unless it has been requested to be returned for investigation.  If a device (i.e., tubing, 
cassette, pump) is requested to be returned for further investigation, instructions will be 
provided.  All pumps will be returned using instructions provided.


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11.0
Study Assessments (Criteria for Evaluation) and 
Flow Chart
Final assessments from the previous open-label LCIG study will serve as the baseline 
assessments for this study.  All assessments must take place within a window of ± 14 days 
from the scheduled visit day unless otherwise noted.
In the event a study subject transfers to LCIG commercial product, all assessments under 
termination assessments in the Flow Chart of Assessments must be completed prior to 
transferring to commercial product, with the exception of the removal of the PEG tube 
which will remain in place.
11.1
Safety Assessments
11.1.1
Adverse Events
Adverse events will be recorded at each visit.  Requirements for collecting, recording and 
reporting of AEs are described in Section 13.0.  Each subject is to be evaluated at the 
Early Termination/End of Study visit.  Should any AE be identified at this visit, the 
Investigator will continue to follow the subject as described in Section 12.1.2.
11.1.2
Sleep Attacks
To prospectively monitor for the possible development of sleep attacks the following 
question will be asked of subjects at the times indicated in Table 2:
Since your last visit or last time this question was asked, have you experienced any events 
in which you fell asleep suddenly or unexpectedly, including while engaged in some 
activity (e.g., eating/drinking, speaking, or driving) or a rest, with or without any previous 
warning of sleepiness?
●
If yes, what specifically happened?
●
How many times did you experience such events?
●
What were you doing at the time of each event?


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●
Prior to each event did you experience any sleepiness or drowsiness?  If yes, 
please explain/clarify.
●
How long did each event last?
●
Did you suffer any "bad" outcome/problem from each falling asleep event?
11.1.3
Assessment for Melanoma
A comprehensive assessment for the presence of melanoma must be performed at yearly 
intervals, including at the Early Termination/End of Study, by a dermatologist 
experienced with the diagnosis of the condition.  If a suspicious lesion is present, a biopsy 
should be obtained for proper diagnosis and subjects should be referred to appropriate 
follow-up treatment, if necessary.  Subjects who have a melanoma present at the start of 
the study, or who develop a melanoma during the course of the study should be 
discontinued from participation and referred for proper follow-up care.
11.1.4
Assessment of Impulsive Behavior
To monitor for the development of intense impulsive behavior, the Minnesota Impulsive 
Disorders Interview (MIDI) will be administered at 6 month intervals during the course of 
the subject's involvement in the study, and at the time of the subjects' termination from the 
study.  In addition, the Investigator should ask the subjects to inform him/her immediately 
if they experience new or increased gambling urges, increased sexual urges, or other 
intense urges while taking LCIG.
If the subject's impulsivity is judged to be clinically significant, in the judgment of the 
Investigator, the subject will be discontinued from participation in the study and referred 
for appropriate follow-up care.
The General Information and Background Module sections of the MIDI do not need to be 
completed.


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11.1.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS)16 is a systematically administered 
instrument developed to track suicidal adverse events across a treatment study.  The 
instrument is designed to assess suicidal behavior and ideation, track and assess all 
suicidal events, as well as the lethality of attempts.  Additional features assessed include 
frequency, duration, controllability, reason for ideation, and deterrents.  The C-SSRS is 
considered a low-burden instrument, as it takes less than 5 minutes to administer.  Raters 
will receive instruction on the administration of the C-SSRS assessment scales prior to 
administration of the scales.  The C-SSRS will be administered at the times outlined in 
Table 2.
Subjects expressing suicidal ideation with plan, either by answering "yes" to questions 4 
and/or 5 to the suicidal ideation portion of the C-SSRS or via clinical interview, will be 
evaluated immediately by the Investigator or another medically qualified individual 
(M.D., D.O.).  The Medical Monitor must be notified and the subject will be discontinued 
from participation in the study.  The subject will be referred for appropriate psychiatric 
follow-up treatment, if necessary, per the judgment of the Investigator or the medically 
qualified individual.  The Medical Monitor will also be notified.  In addition, if the subject 
expresses suicidal ideation or suicidal behavior at any time during the course of the study, 
the subject should be discontinued from participation in the study and referred for proper 
psychiatric follow-up care.  The Investigator and the Medical Monitor should be notified 
immediately as well. 
Under no circumstances should a subject who has positively endorsed or expressed 
suicidal ideation or behavior be left alone, be allowed to exit the site, or go home 
before a qualified medical professional has evaluated the subject's risk.
The "Already Enrolled Subjects" C-SSRS will be the first assessment scale administered 
to the subject.  At each subsequent assessment, the "Since Last Visit" C-SSRS scale 
should be administered.


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If the subject has previously completed the "Already Enrolled Subjects" scale in the 
S187.3.003 study, the subject should complete the "Since Last Visit" scale at all 
scheduled time points outlined in Table 2 in this study.  For subjects with a C-SSRS 
completed at their S187.3.003 final visit, that S187.3.003 final visit C-SSRS assessment 
will be considered baseline for the S187.3.005 study.  For all other subjects, the 
first C-SSRS assessment completed in this study will serve as baseline.
11.1.6
Vital Signs
Orthostatic vital signs including pulse, blood pressure, and body temperature will be 
measured at the times indicated in Table 2.  Temperature measurements should be 
assessed by a consistent method (e.g. all oral or all ear [tympanic membrane] 
measurements) and by the same method as baseline, if baseline is available.  Weight will 
be measured at the times indicated in Table 2.
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate are to be 
measured while the subject is supine (after 3 to 5 minutes) and standing (after 2 minutes).
11.1.7
Physical Examination
A physical exam as per usual practice will be performed at 6 month intervals, and at the 
time of the subjects' termination from the study.  Any relevant findings are to be recorded 
on the Adverse Events Form in the eCRF.
11.1.8
Neurological Examination
A Neurologic Examination including light touch and pinprick sensation, vibratory 
sensation, deep tendon reflexes, and strength assessments will be performed at the times 
indicated in Table 2.  The Neurologic Examination will be done during "On" time.
Any abnormalities or symptoms identified during treatment will be recorded as adverse 
events.


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The neurological examination will assess:
●
Cranial nerves – assessment of cranial nerves II–XII, excluding fundoscopic 
examination
●
Motor system – assessment of tone, strength and abnormal movements
●
Sensory system – including light touch, pinprick, joint position and vibratory 
sense
●
Reflexes – assessment of deep tendon reflexes and plantar responses 
(Babinski sign)
●
Coordination – assessment of upper and lower extremities
●
Gait – assessment of base and tandem gait
●
Station – assessment of posture and stability
11.1.9
Laboratory Evaluations
The laboratory evaluations listed in Table 1, including special tests for vitamin 
deficiencies (Folic Acid, Vitamin B6, Vitamin B12, Methylmalonic Acid (MMA), and 
Homocysteine) will be performed by a central laboratory to be designated by Sponsor, at 
the times indicated in Table 2.  No other formal assessment of laboratory evaluations is 
scheduled, but will be done as subject's condition mandates and performed as an element 
of routine care.


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Table 1.
Laboratory Evaluations
Hematology
Blood Chemistry
Special Tests
Urinalysis
Hemoglobin
Hematocrit
White blood count 
(WBC) with differential
Erythrocyte count (RBC)
Platelet count
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
Mean corpuscular 
hemoglobin 
concentration (MCHC)
Glucose
Creatinine
Creatinine kinase
Alkaline phosphatase
Total bilirubin
Serum glutamic-
pyruvic transaminase
(SGPT/ALT)
Serum glutamic-
oxaloacetic 
transaminase 
(SGOT/AST)
Gamma-glutamyl 
transpeptidase 
(GGT)
Total protein
Uric acid
Calcium
Sodium
Potassium
Chloride
Serum urea nitrogen 
(BUN)
Bicarbonate
Lactate dehydrogenase 
(LDH)
Total cholesterol
Triglycerides
Albumin
Pregnancy Test for 
applicable subjectsa
Beta human chorionic
gonadotropin 
(β-hCG)
Folic Acid, 
Vitamin B6, 
Vitamin B12, 
Methylmalonic Acid 
(MMA), and 
Homocysteine levels
pH
Specific Gravity
Glucose
Protein
Microscopic 
Examination
Urine Pregnancy 
Test -
For subjects who are 
of child-bearing 
potential, a negative 
urine pregnancy test 
is required on the 
day of the procedure 
prior to any 
radiological check 
of tube placement.
a.
For all females of child-bearing potential, at end of study.
11.1.10
Electrocardiograms
A single standard 12-lead ECG will be performed at the times indicated in Table 2.  All 
ECGs will be reviewed by a local reader, whose interpretation will be entered in the 


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eCRF and attached to the ECG form along with comments on the clinical significance of 
any abnormalities.  Any change from the previous ECG will be noted on the eCRF in the 
Comments section.  If clinically significant abnormalities in the ECG are found, the 
subject's ECG will be repeated at medically appropriate intervals until it stabilizes or 
returns to acceptable levels.
11.1.11
PEG-Site
The tube insertion site, including the stoma, will be inspected at each Study Visit.
11.1.12
Radiological Check of Tube Placement
Tube placement will only be checked if there is a clinical indication that the tube has been 
displaced.  The tube will be repositioned to the original placement as needed.  It is 
required that women of childbearing potential should have a negative pregnancy test 
immediately prior to the radiological examination to check tube placement.
11.1.13
Complications of the Infusion Device
The tube insertion site, including the stoma, will be inspected at each Study Visit.  Details 
surrounding complications related to the infusion device (e.g., tubing kinks, tubing 
displacement, tubing connector problems, and pump technical difficulties) will be 
collected with regard to the inner tube, outer tube and the pump.  Product Quality 
Complaints concerning devices and cassettes should be recorded on the Product Quality 
Complaint Form and the source documents.  Product Quality Complaints must be reported 
immediately (within 24 hours of the study site's knowledge of the event) by fax to 
Quintiles Pharmacovigilance (Pharmacovigilance fax numbers are found in 
Section 12.2.1).
11.1.14
Yearly Check of PEG Site by Gastroenterologist
On a yearly basis, at a minimum, an assessment will be made of the need for a 
replacement of the PEG-J.  The frequency of replacement should be in accordance with 
local practice.


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11.2
Efficacy Measurements
Efficacy will be assessed using the Parkinson's Disease Diary©, UPDRS, and the PDQ-39.
Appropriate study site personnel must be trained on the use of all scales used in this study.
11.2.1
Parkinson's Disease Diary (Symptom Diary)
The core of the Parkinson's Disease Diary (PD Diary) is the tool that the subject will use 
to record Parkinsonian symptoms.  The subject and/or caregiver will be prompted to 
answer the PD Diary whether the subject has been "ON," "OFF," or "ASLEEP" and what 
has been the severity of the dyskinesias (troublesome or not troublesome).  On PD Diary
recording days, subjects will be instructed to make an entry upon waking and every 
30 minutes during their normal waking time.
Study site staff should make a call to the subjects in advance of their clinic visit to review 
with them the need to complete the PD Diary for the visit.
The PD Diary is to be recorded at the times indicated in Table 2.
Subject Training Requirements
During the initial LCIG study the subject and caregiver, if applicable, were required to 
have diary training which included training of how to understand PD symptomatology and 
how to complete the PD Diary.  A refresher training will be provided to the subjects and 
their caregivers.
Site personnel should emphasize the importance of completing the PD Diary at half-hour 
time points in real time during waking hours to ensure true evaluation of the subject's 
condition.
11.2.2
UPDRS
The United Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool 
to follow the longitudinal course of Parkinson's disease.  To be qualified by the Sponsor, 


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all raters must have participated in the Rater Training and have a current valid Rater 
Certificate.  The UPDRS is made up of the following sections:
●
Part I – Mentation, Behavior, and Mood
●
Part II – Activities of Daily Living
●
Part III – Motor Examination
●
Part IV – Complications of Therapy (including dyskinesias)
●
Part V – Modified Hoehn and Yahr Staging
●
Part VI – Schwab and England Activities of Daily Living Scale
Some sections require multiple grades assigned to each extremity.  UPDRS total score 
ranges from 0 to 176, with 176 representing the worst (total) disability, and 0 no 
disability.  Additionally, Questions 32, 33, and 34 on UPDRS will be totaled to evaluate 
dyskinesias.  
The complete UPDRS (all sections) should be completed at the times indicated in Table 2.
The complete UPDRS will be done within 1 to 4 hours after the first morning dose of trial 
medication during LCIG treatment.  
UPDRS Rater Training
The UPDRS assessments will be administered only by individuals qualified by the 
Sponsor and rater training vendor.  
Prior to administration of respective scale(s), designated raters (Investigator or an 
experienced and medically qualified study site designee (e.g., RN, NP, PA, DO, MD, or 
PhD) assigned by the Investigator) must be certified in the use of the UPDRS.  The 
objective of this certification/training is to ensure uniformity across sites in the 
administration and scoring of these assessments. 
AbbVie, in conjunction with the rater training vendor, will determine the minimum rater 
qualifications for the rating scales.  All raters must meet these qualifications prior to 


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participation in the training process.  The qualifications of the raters will be verified 
through the training vendor.  Qualified raters will be certified or re-certified based on 
prior LCIG study training.  Individual exceptions to these requirements must be approved 
by the Sponsor via the training vendor.
Only those persons who have been trained and certified as raters for this study may rate 
the subjects.  Raters who become involved in the study after the initial training will not be 
permitted to perform study ratings until they have satisfactorily completed an 
individualized training program designed by the rater training vendor, approved by 
AbbVie, and supervised by the Investigator or his/her designee.  Raters may be reassessed 
periodically throughout the study.
11.2.3
PDQ-39
The Parkinson's Disease Questionnaire (PDQ-39) is a disease-specific instrument 
designed to measure aspects of health that are relevant to subjects with PD, and which 
may not be included in general health status questionnaires.  The PDQ-39 is a 
self-administered questionnaire that comprises 39 items addressing the following 
eight domains of health that subjects consider to be adversely affected by the disease:
●
Mobility (e.g., fear of falling when walking)
●
Activities of daily living (e.g., difficulty cutting food)
●
Emotional well-being (e.g., feelings of isolation)
●
Stigma (e.g., social embarrassment)
●
Social support
●
Cognition
●
Communication
●
Bodily discomfort
The PDQ-39 summary index ranges from 0 to 100, where lower scores indicate a better 
perceived health status.  Higher scores are consistently associated with the more severe 
symptoms of the disease such as tremor and stiffness.  In addition to the summary index, 


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the results can be presented as eight discrete domain scores.  The PDQ-39 will be 
completed at the times indicated in Table 2.
11.3
Other Assessments
Informed Consent
Voluntary written informed consent must be obtained from each subject (and if 
appropriate, their caregiver) prior to performing any study-related procedures (see 
Section 4.3).  If the subject does not have the capacity to provide informed consent, full 
informed consent must be obtained from the subject's legally authorized representative.  
Consenting will be performed according to local regulations.
Concomitant Medication
Concomitant medication will be recorded at each study visit.  All medication taken by the 
subject during the study (from signing the Informed Consent form through post-study 
follow-up) is to be recorded on the Concomitant Medication eCRF form, except for study 
drug.
Determination of Continued Benefit
A standard neurological exam should be performed every 6 months to evaluate the 
subject's condition.  The decision to continue on LCIG treatment is based on the Principal 
Investigator's clinical judgment.
Daily Dosing Diary (US sites only)
Subjects will complete a Daily Dosing Diary on the days indicated in Table 2.  The diary 
will include the date and actual clock time of all levodopa-carbidopa intestinal gel 
infusions (including pump start time, pump stop time and the time of any extra dose 
administration) and all oral levodopa/carbidopa doses.


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Study site staff should make a call to the subjects in advance of their clinic visit to review 
with them the need to complete the Daily Dosing Diary for the visit.
The subject or a caregiver should complete a Daily Dosing Diary for study drug 
administration on the days indicated in Table 2.
11.4
Appropriateness of Measurements
The PD Diary, UPDRS, and PDQ-39 are currently accepted and validated methods of 
evaluating subjects with PD.  All safety assessments are standard measures used in 
pharmaceutical research.
11.5
Primary Outcome Measure
Not applicable.
11.6
Flow Chart of Study Assessments
All study assessments will be conducted as indicated in Table 2, which displays the 
frequency and timing of all measurements.  Subject visit days should ideally match the 
target clinic visit days; however, a ± 14 day visit window will be allowed as necessary for 
the 6 Monthly visits and a ± 7 day visit window will be allowed for clinical supply visits.  
Every attempt should be made to bring the subject back on the target visit day.


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Table 2.
Flow Chart of Study Assessments
Visit
Baseline
6 Monthly 
Visit
Termination/ 
Transfer to 
Commercial
Follow-up*
Day
Final Assessment 
in Previous Study
+/– 14 Days
--
Termination Visit 
+ 7 Days
Informed consent
X
Inclusion/exclusion 
X
Physical exam
Xa
X
X
Neurological Exam
Xa
X
X
Weight
Xa
X
X
Vital signs
Xa
X
X
X
12-lead ECG
Xa
Xb
X
Clinical labs
Xa
Xb
X
Folic Acid, Vitamins B6, 
B12, Methylmalonic Acid 
(MMA), and 
Homocysteine Levels
Xa
X
X
β-HCGc
Xa
X
X
Adverse events**
Xa--------------------------------------------------------------------X
Concomitant medication
Xa
X
X
X
Sleep attacks
Xa
X
X
Melanoma check
Xa
Xd
X
Determination of 
continued benefit***
X
X
MIDI 
Xa
X
X
C-SSRSf
Xa
X
X
X
Complications with 
infusion device
Xa
X
X
Inspection of stoma
Xa
X
X
X
Assessment of the need to 
replace PEG-J****
X
Xd
Dispensing of study drug
X-----Every 6 weekse-----
Daily Dosing Diaryg
X
X


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Table 2.
Flow Chart of Study Assessments (Continued)
Visit
Baseline
6 Monthly 
Visit
Termination/ 
Transfer to 
Commercial
Follow-up*
Parkinson's Disease Diaryg
X
X
UPDRSh
X
X
PDQ-39h
X
X
Removal of PEG*****
X
*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug 
after termination.
**
Collection of adverse events is an ongoing and continuous process, not only occurring during site visits.
***
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
****
On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice. 
***** For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to 
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
a.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
b.
Will be done as clinically indicated.
c.
For women of childbearing potential.
d.
Assessment performed once yearly.
e.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits may take place at the hospital 
pharmacy and are for the purpose of dispensing clinical study drug and ancillary supplies.  Other assessments may 
be completed during these visits if required.  When scheduling the 6 weekly drug dispensing visits, the site should 
always refer back to the baseline visit.  Every attempt should be made to pick up drug on the original targeted dates 
(±7 days).
f.
The "Already Enrolled Subjects" C-SSRS is to be the first assessment scale administered to the subject.  At each 
subsequent assessment, the "Since Last Visit" C-SSRS scale should be administered.  If the subject has previously 
completed the "Already Enrolled Subjects" scale in the S187.3.003 study, the subject should complete the "Since 
Last Visit" scale at all scheduled time points outlined in Table 2 in this study.  For subjects with a C-SSRS 
completed at their S187.3.003 final visit, that S187.3.003 final visit C-SSRS assessment will be considered 
baseline for the S187.3.005 study.  For all other subjects, the first C-SSRS assessment completed in this study will 
serve as baseline.
g.
The Daily Dosing Diary and the Parkinson's Disease Diary will be completed by subjects or their caregivers for the 
3 consecutive days prior to each clinic visit at US sites only.
h.
The UPDRS and the PDQ-39 will be completed at US sites only.


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12.0
Adverse Events
12.1
Adverse Events and Adverse Drug Reactions
Definition Adverse Event (AE)
Any untoward medical occurrence in a subject or clinical investigation subject 
administered a medicinal product (or a system consisting of drug, device and surgical 
procedure as with LCIG) and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom (including an AE 
occurring from drug abuse, an AE occurring from drug withdrawal and any failure of 
expected pharmacological action) or disease temporally associated with the use of a 
medicinal product or device, whether or not considered related to the medicinal product or 
device.
Definition Adverse Drug Reaction (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered ADRs.  The 
phrase "response to a medicinal product" means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out.
Regarding marketed medicinal products:  a response to a drug which is noxious and 
unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function.
An unexpected ADR is an ADR, the nature or severity of which is not consistent with the 
applicable product information, such as the Investigator's Brochure (IB).


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Product Quality Complaint
A Product Quality Complaint is a written, electronic or oral communication that alleges 
deficiencies related to the identity, physical aspects, potency, expressed lack of effect 
(LOE), purity, packaging, durability, reliability, safety or performance of a product 
manufactured by or for the Sponsor that has been placed on the market or an 
investigational product that is used in a clinical study, see Section 12.2.1.
Product Quality Complaints with regard to the medical devices (device complaints) 
include, but are not limited to Incidents.
Product Quality Complaints concerning devices, tubing and cassettes must be reported 
immediately (within 24 hours of the study site's knowledge of the event) by fax to 
Quintiles Pharmacovigilance, see Section 12.2.1 for the fax numbers.
Incident
An Incident is any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly might lead or have led to the death of a subject or user or of other 
persons or to a serious deterioration in their state of health.
A serious deterioration in state of health can include:
a) Life-threatening illness
b) Permanent impairment of a body function or permanent damage to a body 
structure
c) A condition necessitating medical or surgical intervention to prevent a) or b) 
e.g., clinical relevant increase in the duration of a surgical procedure, a condition 
that requires hospitalization or significant prolongation of existing hospitalization
d) Fetal distress, fetal death or any congenital abnormality or birth defects


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Not all incidents lead to death or serious deterioration in health.  The non-occurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of health care personnel.
It is sufficient that:
●
An Incident associated with the device happened, and
●
The Incident was such that, if it occurred again, it might lead to death or 
serious deterioration in health.
Device complaints which have to be reported are side effects, malfunction or deterioration 
in the characteristics and/or performance of a device, inadequacy in the labeling or the 
instructions for use which do not fulfill the criteria of an Incident as well as use errors and 
abnormal use.
12.1.1
Recording of Adverse Events
All AEs should be recorded on the Adverse Events eCRF and source documents.
In addition Product Quality Complaints concerning devices, cassettes, and/or LCIG 
should be recorded on the Product Quality Complaint and Incident form, and the source 
documents.  Product Quality Complaints must be reported immediately (within 24 hours 
of the study site's knowledge of the event) by fax to Quintiles Pharmacovigilance 
(Pharmacovigilance fax numbers are found in Section 12.2.1).  Product Quality 
Complaints concerning devices should also be recorded on the eCRF.  Product Quality 
Complaints leading to a subject's health impairment should be recorded in the eCRF as an 
AE.
In order to avoid vague, ambiguous or colloquial expressions, the AE should be recorded 
in standard medical terminology rather than the subject's own words.  Whenever possible, 
the Investigator should group together the signs and symptoms which constitute a single 
diagnosis into a single term which reflects the actual diagnosis.


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The existence of or change in an AE may be concluded due to the necessity to administer  
a concomitant medication, from a spontaneous report of an event from the subject, from 
the physical examination or from the results of special tests such as ECG, 
electroencephalograms, laboratory assessments or other study- specified tests (source of 
AE).
AEs which occur in the specified pre-treatment through the follow-up period, regardless 
of the interval prior to the first administration of the study drug or the interval since the 
last administration of the study drug, will be handled as any other AE occurring during the 
treatment with study drug.  Following termination of LCIG treatment, including the 
removal of PEG-J, AEs should continue to be reported for 30 days, irrespective of the 
reason for termination (Early Termination or the end of the study).
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to 
the therapeutic system.  The action taken with the therapeutic system, the concomitant 
treatment/therapy introduced and the outcome, as well as whether the event led to study 
termination, will also be recorded.
Severity
The severity of the AE should be characterized as "mild, moderate or severe" according to 
the following definitions:
●
Mild events are usually transient and do not interfere with the subject's daily 
activities.
●
Moderate events introduce a low level of inconvenience or concern to the 
subject and may interfere with daily activities.
●
Severe events interrupt the subject's usual daily activity.


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Drug-Event Relationship
For the assessment of drug event relationship, LCIG should be considered a therapeutic 
system consisting of drug, devices and implantation procedure.  Causality assessments are 
always made over the system as a whole.
The causal relationship between the therapeutic system and the AE should be 
characterized according to the following:
●
Unrelated – there is not a reasonable possibility that the therapeutic system 
caused the AE.
●
Unlikely – suggests that only a remote connection exists between the 
therapeutic system and the event.  Other conditions, including concurrent 
illness, progression or expression of the disease state or reaction to 
concomitant medication, appear to explain the AE.
●
Possible – suggests that the association of the AE with the therapeutic system 
is unknown; however, the event is not reasonably supported by other 
conditions, regardless of whether the adverse event might be related to an 
associated condition or other concomitant treatment.
●
Probable – suggests that a reasonable temporal sequence of the AE with the 
therapeutic system exists and, in the Investigator's clinical judgment, it is 
likely that a causal relationship exists between the therapeutic system and the 
AE, and other conditions (concurrent illness, progression or expression of the 
disease state, or concomitant medication reactions) do not appear to explain 
the AE.
Outcome
The outcome of the adverse event should be classified according to the following 
definitions:
●
Recovered/resolved:  The event has resolved (no further symptoms are present 
and no treatment is being received by the subject).


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●
Recovered/resolved with sequelae:  The event has resolved, but there may be 
lingering effects present (e.g., a scar following a cut or abrasion).
●
Fatal:  The subject died as a result of the event.  This code should only be used 
for the event that caused the death, not any event that was present at the time 
of the subject's death.  Fatal events require immediate reporting to the Sponsor 
(or an authorized representative).
●
Unknown:  May only be used in the event that the subject is lost to follow-up 
and no reliable data can be obtained.
All efforts should be made to classify the AE according to the above categories.
Note:  When the AE is ongoing, the outcome will remain blank on the Adverse Events 
eCRF.
12.1.2
Follow-Up of Adverse Events
All AEs occurring during the study are to be followed-up in accordance with good 
medical practice until resolved or judged no longer clinically significant, or if a chronic 
condition, until fully characterized.  All follow-up results are to be reported to the Sponsor 
(or an authorized representative).
12.1.3
Follow-Up of Product Quality Complaints
The Product Quality Complaints occurring during the study are to be followed up until 
resolved.  All follow-up results are to be reported to the Sponsor (or an authorized 
representative).
12.1.4
Adverse Events of Special Interest
Adverse events of special interest (AESI) for LCIG are:
●
Risks of PEG-J insertion
●
Long-term complications of PEG-J
●
Device associated gastrointestinal disorders during long-term therapy


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●
Cardiovascular fatalities
●
Aspiration including aspiration pneumonia
●
A diagnosis of peripheral polyneuropathy; axonal, demyelinating or mixed 
type
●
Possible symptoms of peripheral polyneuropathy such as sensory disturbances 
or loss of strength, which from their course and clinical presentation or from 
their response to medication could be precursors of polyneuropathy
●
Clinically significant weight loss
A standard panel of examinations will be suggested to the Investigators if one of the study 
subjects develops signs and symptoms of polyneuropathy.  The panel should be 
considered as a basic recommendation and the selection of additional diagnostic tools is at 
the discretion of the Investigator, depending on the clinical presentation of the individual 
subject.
For AESIs, serious and nonserious, meeting pre-defined criteria, specific questionnaires 
will be used to standardize the collection of follow-up information.
All cases of clinically significant weight loss and possible symptoms or precursors of 
polyneuropathy (serious and non serious) should be reported on the Report for SAEs and 
AESIs (Yellow Form) to the Sponsor (or an authorized representative) within the 
expedited timelines applicable for SAEs.
12.2
Serious Adverse Events (SAEs) and Serious Adverse Drug 
Reactions (SADRs)
Definition Serious Adverse Event (SAE)/Serious Adverse Drug Reaction (SADR)
Any untoward medical occurrence that at any dose:
●
Results in death
●
Is life-threatening (an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)


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●
Requires inpatient hospitalization or prolongation of an existing hospitalization
●
Results in persistent or significant disability/incapacity
●
Is a congenital anomaly/birth defect
In addition, medical and scientific judgment should be exercised in deciding whether 
other conditions should also be considered serious, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization, but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed above.  These should also be considered serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
During the course of the study:
If not associated with significant worsening of PD symptoms, a hospitalization for dose 
adjustments of LCIG will not be regarded as an SAE.  A hospitalization because of a 
Product Quality Complaint such as a device dislocation without AE (i.e., without health 
impairment) will not be regarded as an SAE.
12.2.1
Reporting Serious Adverse Events
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the therapeutic system, must be reported immediately (within 24 hours of 
the study site's knowledge of the event) by telephone or fax to the Sponsor or the 
Sponsor's authorized representative (phone or fax numbers are listed below).
Additionally, Product Quality Complaints concerning devices and cassettes must also be 
reported immediately (within 24 hours of the study site's knowledge of the event) by fax 
to Quintiles Pharmacovigilance at the following numbers:


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Quintiles Pharmacovigilance toll free numbers:
Australia
Phone: 1 800 142 945
Fax:  1 800 142 946
Israel
Phone:  809452016
Fax:  1 80 945 201
Italy
Phone:  800 8 747 41
Fax:  800 8 747 51
New Zealand
Phone:  0 800 44 5044
Fax:  0 800 44 5043
Poland
Phone:  00 800 353 1 203
Fax:  00 800 353 1 204
Portugal
Phone:  800 85 32 08
Fax:  800 85 32 09
Russia
Phone:  AT&T access code 
363 2400 (Moscow) or 8 pause 
495 363 2400 (Outside Moscow) or 
8 pause 812 363 2400 (Outside St. 
Petersburg) or  8 + pause + 10-800-
110-1011 (all other places)
+ Pause
+ Phone #:  877 264 10 40
Fax:  AT&T access code 
363 2400 (Moscow) or 
8 pause 495 363 2400 
(Outside Moscow) or 
8 pause 812 363 2400 
(Outside St. Petersburg) or 
8 + pause + 10-800-110-
1011 (all other places)
+ Pause
+ Fax #:  877 264 10 39
Thailand
AT&T access code 001 999 111 11 
or 1 800 001 33 
Phone:  877 264 10 40
Fax:  877 264 10 39
UK
Phone:  0 800 834 450
Fax:  0 800 132 079
US and Canada
Phone:  866 366-9790
Fax:  866 490-2648
Quintiles Pharmacovigilance non-toll free number:
All Ex-US 
countries
Phone:  00 353 1 819 55 11
Fax:  00 353 1 809 9501
The report will contain as much available information concerning the SAE and/or Product 
Quality Complaint to enable the Sponsor (or an authorized representative) to file a report 
that satisfies regulatory reporting requirements.  In addition to the initial 24-hour report, a 
completed, separate SAE Report and/or Product Quality Complaint form is to be sent to 


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the Sponsor (or an authorized representative) via fax or mail within 48 hours of the event.  
These timelines apply to initial reports of SAEs and to all follow-up reports.
All SAEs and/or Product Quality Complaints will be recorded on the SAE Report form 
and/or Product Quality Complaint form, the Adverse Events form in the eCRF, and source 
documents.  Criteria for documenting the relationship to the therapeutic system as well as 
severity and outcome will be the same as those previously described.
All SAEs that are spontaneously reported within 30 days of a subject's last visit are to be 
collected and reported as previously described.
12.2.2
Reporting of Serious Adverse Drug Reactions and 
Suspected Unexpected Serious Adverse Drug Reactions to 
Regulatory Authorities and Investigators
All serious adverse drug reactions will be subject to expedited reporting per local 
requirements and regulations.  All suspected unexpected serious adverse drug reactions 
(SUSARs) will be subject to expedited reporting and any additional local requirements 
and regulations.  Additionally, post-study SUSARs that occur after the subject has 
completed a clinical study and are reported by the Investigator to the Sponsor (or an 
authorized representative) qualify for expedited reporting.  Expectedness is assessed 
according to the Investigator's Brochure (IB) for LCIG.14
The Sponsor (or an authorized representative) is responsible for submitting reports of 
SUSARs to the appropriate national regulatory authorities within the required reporting 
period.  All Investigators participating in ongoing clinical studies with the therapeutic 
system will be notified by the Sponsor (or an authorized representative) of all SUSARs 
that require prompt submission to the IEC/IRB.  The Sponsor (or an authorized 
representative) or the Investigator (according to national provisions) is responsible for 
notifying the IECs/IRBs in writing of the SUSARs within the required reporting 
timelines.  Copies of the notification will be maintained by both the Investigator and the 
Sponsor (or an authorized representative) in the study documentation files.


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12.3
Pregnancies
If a subject should become pregnant during the study, the event will be reported on a 
Pregnancy form within 1 working day of the study site's knowledge of the pregnancy.  
The Pregnancy form is to be faxed to the Sponsor (or an authorized representative) at the 
contact numbers listed in Section 12.2.1.
The pregnancy evolution and outcome (i.e., the health status of the newborn), is to be 
reported on a Pregnancy Outcome form and reported to either the Sponsor (or an 
authorized representative) within 1 working day of the study site's knowledge of the 
event.
13.0
Statistical Methods and Determination of Sample 
Size
Data handling will be the responsibility of Quintiles, Inc.  The data will be inspected for 
inconsistencies by performing validation checks.  Any inconsistencies found will be 
resolved by the monitor after contacting the Investigator.  When the data in the database 
are considered clean and the subjects allocated to subject samples in a data review, the 
database will be locked to prevent unauthorized access.  Next, the database will be made 
available as SAS® files for statistical analysis.
All details regarding the statistical analysis and the preparation of tables, listings and 
figures will be described in the Statistical Analysis Plan prepared by Quintiles, Inc. and 
approved by the Sponsor before database lock.
The statistical analysis will be performed by Quintiles, Inc.
13.1
Statistical Objective
The primary statistical objective of this study will be to evaluate the long-term safety of 
LCIG. 


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13.2
Analysis Populations
Definitions of analysis populations:
1.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of 
study medication in this study.  The Safety Population will be used for all analyses 
unless noted otherwise.
2.
Efficacy Population:
The Efficacy Population includes all subjects who have taken at least one dose of 
study medication in this study and have at least one efficacy assessment in this 
study.
This is an open-label study with a single, active treatment group; all subjects in this study 
will receive LCIG.
13.3
Statistical Methods 
Safety Analysis
The Safety Population will be used for the analysis of the safety and tolerability data.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  A treatment-emergent adverse event (TEAE) is defined as any adverse event 
that begins or worsens in severity on or after the first dose of study drug in the current 
study and within 30 days of the end of LCIG treatment in the current study.  For subjects 
transferring to commercial product, the end of treatment in the current study will be the 
last dose of study drug.  For subjects who are discontinuing LCIG treatment, the end of 
treatment in the current study will be the removal of the PEG-J tube.  The following 
summaries of TEAE's will be prepared:
●
Incidence of treatment-emergent adverse events
●
Incidence of treatment-emergent serious adverse events


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●
Incidence of treatment-emergent adverse events resulting in study termination
●
Incidence of treatment-emergent adverse events of special interest
The following additional analyses of safety will also be prepared:
●
Summary of vital sign and weight values and mean change from Baseline over 
time
●
Incidence of potentially clinically significant vital sign and weight values
●
Summary of clinical lab values and mean change from Baseline to Endpoint
●
Summary of special lab values and mean change from Baseline over time
●
Incidence of potentially clinically significant clinical lab values
●
Summary of MIDI at Baseline and during treatment
●
Summary of C-SSRS
●
Incidence of device complications
Efficacy Analysis
The Efficacy Population will be used for analyses of efficacy.  The mean change from 
baseline to endpoint will be summarized for the following efficacy endpoints.
●
"Off" time as measured by the Parkinson's Disease Diary
●
"On" time without troublesome dyskinesia (sum of "On" time without 
dyskinesia and "On" time with non-troublesome dyskinesia) as measured by 
the Parkinson's Disease Diary
●
UPDRS total score, Parts I, II, III and IV scores, and dyskinesia item score
●
PDQ-39 summary index and domain scores
For the analysis of change from baseline in efficacy measures, each subject's baseline will 
be their baseline measure in the first LCIG study in which they participated 
(e.g., Study S187.3.001, S187.3.002 or S187.3.004).


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Additional Analysis
Subject disposition will be summarized including the primary reason for premature 
discontinuations and a listing of all subjects not included in the safety population.
Descriptive statistics will be provided for demographics and baseline characteristics.
Concomitant medication use will be summarized over time.
Baseline and Endpoint
Unless noted otherwise, the baseline value for a variable is defined as the last non-missing 
value collected in the current study or the previous open-label LCIG study before the 
first dose of study drug in the current study.
The endpoint value for a variable is defined as the last non-missing value assigned to the 
treatment period in the current study for the subject.  For subjects transferring to 
commercial product, the end of treatment in the current study will be the last dose of study 
drug.  For subjects who are discontinuing LCIG treatment, the end of treatment in the 
current study will be the removal of the PEG-J tube.
13.4
Alpha Level Tested
Not applicable.
13.5
Sample Size
This is an open-label extension study.  All subjects in a country where LCIG is not 
commercially available will be eligible to enroll if they meet the study's inclusion criteria 
and exclusion criteria.
14.0
Investigator Obligations
The Investigator agrees to conduct the clinical study in compliance with this protocol after 
the approval of the protocol by the IEC/IRB in compliance with local regulatory 


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requirements.  The Investigator and the Sponsor will sign the protocol to confirm this 
agreement.
14.1
Essential Documents
The Investigator is responsible for providing and maintaining essential study documents.  
Essential study documents are those documents that individually and collectively permit 
the evaluation of the conduct of the study and the quality of the data produced.  These 
documents serve to demonstrate the compliance of the Investigator and the Sponsor (or an 
authorized representative) with the standards of GCPs and with all applicable national 
regulatory requirements.
Essential study documents will include regulatory documents as well as source documents 
which are original documents, data and records of clinical findings, observations and 
other activities in a clinical study necessary for the reconstruction and evaluation of the 
study.  Source documents will include hospital records, clinical and office charts, 
laboratory notes, memoranda, subject diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files and records kept at the pharmacy, at the 
laboratories and at medical/technical departments involved in the clinical study.
The Investigator agrees to allow direct access to all essential clinical study documents for 
the purpose of monitoring and/or auditing by the Sponsor (or an authorized 
representative) and inspection by the appropriate national and foreign regulatory 
authorities.
14.2
Electronic Case Report (eCRF) Form Completion
Data reflecting the subject's participation with the therapeutic system under investigation 
will be reported to the Sponsor.  The data will be recorded on the electronic CRF (eCRF) 
or other media provided or approved by the Sponsor.  The eCRF is essentially considered 


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a data entry form and will not constitute the original (or source) medical records unless 
otherwise specified.
The Investigator must submit a completed eCRF for each subject who receives study 
drug, regardless of duration.  All supportive documentation submitted with the eCRF, 
such as laboratory or hospital records, should be clearly identified with the study and 
subject number.  Any personal information, including subject name, should be removed or 
rendered illegible to preserve individual confidentiality.
An electronic data capture (EDC) system, managed by Quintiles, will be used instead of 
paper CRFs to collect data for this study.  Electronic CRFs will allow for data to be 
entered remotely and remote study monitoring.  Instructions on the use of electronic CRFs 
will be provided to the study site.  The Investigator will use an electronic signature to 
document his/her review of the data and acknowledgment that the data are accurate.  
Changes to the electronic CRF will be made only by the Investigator and authorized staff.
Supportive paper documentation should be completed in indelible ink and be legible.  If 
an entry on supportive paper documentation requires change, the correction should be 
made as follows:
●
Draw a single line through the incorrect entry.
●
Enter the correct data and initial and date the change.
Correction fluids, markers, erasure or any form of obliteration on supportive paper 
documentation is not permitted under any circumstances.
14.3
Essential Records Retention
The Investigator should maintain the essential clinical study documents (including eCRFs, 
source documents, clinical drug disposition records, signed subject informed consent 
forms, AE reports and other regulatory documents) as required by the applicable national 
regulatory requirements.  The Investigator is to take adequate measures to prevent 
accidental or premature destruction of these documents.  In the event of accidental 


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destruction, the Investigator should notify the Sponsor (or an authorized representative) 
immediately.
Essential clinical study documents will be retained at least two (2) years after the last 
approval of a marketing application in an International Conference on Harmonisation 
(ICH) region and until there are no pending or contemplated marketing applications in an 
ICH region OR at least two (2) years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents shall be retained 
for a longer period; however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor (or an authorized representative).
The Investigator is required to notify the Sponsor (or an authorized representative) prior to 
changing the location or status of any essential clinical study documents.  The Sponsor (or 
an authorized representative) will be responsible for informing the Investigator as to when 
these documents no longer need to be retained.
14.4
Investigator Agreement
The Investigator is responsible for assuring the proper implementation and conduct of the 
clinical study including those study-related duties delegated to other appropriately 
qualified individuals.  The Investigator and his/her staff will cooperate with the Sponsor 
(or an authorized representative) during monitoring and auditing visits to assist with the 
review of the study data and resolve any discrepancies.
The Investigator will demonstrate due diligence in recruitment and screening of potential 
study subjects.  The enrollment rate should be sufficient to complete the study as agreed 
with the Sponsor (or an authorized representative).  The Sponsor (or an authorized 
representative) is to be notified of any projected delays, which may impact the completion 
of the study.
The Sponsor retains the right to terminate the clinical study at any time for any reason.  In 
such an event, instructions on the requirements for the discontinuation of subjects will be 
provided by the Sponsor (or an authorized representative).


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14.4.1
Investigator's Agreement/Signature
1.
I have received and reviewed the Investigator's Brochure for Levodopa-Carbidopa 
Intestinal Gel.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
Protocol Title:
Open-Label Continuation Treatment Study with Levodopa-Carbidopa 
Intestinal Gel in Subjects with Advanced Parkinson's Disease and 
Severe Motor-Fluctuations Who Have Exhibited a Persistent and 
Positive Effect to Treatment in Previous Studies
Protocol Date:
17 December 2013
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Sponsor Obligations
15.1
Protocol Amendments
Only the Sponsor (or an authorized representative) will make modifications to the clinical 
study protocol, which will be documented in a written amendment that describes all 
changes that will be implemented.  Protocol amendments will be categorized as either 
substantial or non-substantial.
Protocol amendments will be considered substantial when the changes have significant 
impact on:
●
The safety of physical or mental integrity of the subjects
●
The scientific value of the study
●
The conduct or management of the study
●
The quality or safety of any investigational medicinal product or control used 
in the study
Protocol amendments will be considered non-substantial when the changes affect only 
administrative issues with the conduct of the study (e.g., changes in telephone numbers or 
addresses).
The Sponsor (or an authorized representative) will be responsible for notifying the 
appropriate national regulatory authorities in writing of any amendments to the protocol 
prior to the changes being implemented except in those cases where the changes are 
necessary to eliminate an immediate hazard to the clinical study subjects.
Substantial amendments will require written approval by the IEC/IRB prior to being 
implemented by the Investigator at the study site except under those circumstances 
described previously.  Non-substantial amendments will not require approval by the 
IEC/IRB unless requested by the IEC/IRB.


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15.2
Study Monitoring
The study will be monitored by authorized representatives of the Sponsor throughout its 
duration by means of personal visits to the Investigator's facilities and through other 
communications (e.g., telephone calls, written correspondence).  Monitoring visits will be 
scheduled at mutually agreeable times periodically throughout the study and at frequency 
deemed appropriate for the study.
These visits will be conducted to evaluate the progress of the study, ensure the rights and 
well-being of the subjects are protected, check that the reported clinical study data are 
accurate, complete and verifiable from source documents, and the conduct of the study is 
in compliance with the approved protocol and amendments, GCPs and applicable national 
regulatory requirements.  A monitoring visit will include a review of the essential clinical 
study documents (regulatory documents, eCRFs, source documents, drug disposition 
records, subject informed consent forms, etc.) as well as discussion on the conduct of the 
study with the Investigator and staff.  The Investigator and staff should be available 
during these visits to facilitate the review of the clinical study records and 
resolve/document any discrepancies found during the visit.
15.3
Quality Assurance Audits
The Sponsor's (or an authorized representative's) Quality Assurance department may 
conduct on-site audits of all aspects of the clinical study either during the study or after 
the study has been completed.
The clinical study may also be subject to inspection by regulatory authorities (national or 
foreign) as well as the IECs/IRBs to ascertain that the study is being or has been 
conducted in accordance with protocol requirements, GCPs, as well as the applicable 
regulatory requirements.  The site is to contact the Sponsor or representative immediately 
if they are notified of an audit.


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15.4
Annual Reporting
Adverse events will be summarized annually and made available to the IRB/IEC and/or 
authorities upon request.  This includes:
●
Tables and listings of overall AE incidence
●
Tables and listings of AEs that led to discontinuation
●
Tables and listings of SAEs
●
AEs will also be evaluated and submitted as part of the Periodic Safety Update 
Report (PSUR) to regulatory agencies
16.0
Publication Policy
The data generated by this study are confidential information of the Sponsor.  The 
Sponsor will make the results of the study publicly available.  The publication policy with 
respect to the Investigator and study center will be set forth in the Clinical Trial 
Agreement.
17.0
Insurance
Insurance
The Sponsor has obtained liability insurance, which covers this study as required by local 
law and/or national regulations and/or ICH guidelines whichever is applicable.
Applicable for the United States:
Subject Injury
If during the course of this study any injury should occur to the subject as a direct result of 
the taking of the study drug, all medical expenses necessary to treat such injury will be 
paid by the Sponsor provided:  a) the subject follows the study doctor's instructions at all 
times; b) the subject promptly reports any such injury to the study doctor conducting the 
study.  Subject's expenses will not be submitted to their insurance or third-party health 


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care provider/payer.  Financial compensation for such things as lost wages, disability or 
discomfort due to injury is not routinely paid.
18.0
References
1.
Nyholm D, Aquilonius SM.  Levodopa infusion therapy in Parkinson disease:  state 
of the art in 2004.  Clin Neuropharmacol.  2004;27(5):245-56.
2.
Nyholm D, Nilsson Remahl AI, Dizdar N, et al.  Duodenal levodopa infusion 
monotherapy vs oral polypharmacy in advanced Parkinson disease.  Neurology.  
2005;64(2):216-23.
3.
Agid Y, Ahlskog E, Albanese A, et al.  Levodopa in the treatment of Parkinson's 
disease:  a consensus meeting.  Mov Disord.  1999;14(6):911-3. 
4.
Van Laar T.  Levodopa-induced response fluctuations in patients with Parkinson's 
disease:  strategies for management.  CNS Drugs.  2003;17(7):475-89.
5.
Mouradian MM, Heuser IJ, Baronti F, et al.  Pathogenesis of dyskinesias in 
Parkinson's disease.  Ann Neurol.  1989;25(5):523-6.
6.
Stocchi F, Vacca L, Ruggieri S, et al.  Intermittent vs. continuous levodopa 
administration in patients with advanced Parkinson disease.  Arch Neurol.  
2005;62(6):905-10.
7.
Movement Disorder Society.  Management of Parkinson's disease:  an 
evidence-based review.  Mov Disord.  2002;17(Suppl 4):S1-166.
8.
Shoulson I, Glaubiger GA, Chase TN.  On-off response.  Clinical and biochemical 
correlations during oral and intravenous levodopa administration in parkinsonian 
patients.  Neurology.  1975;25(12):1144-8.
9.
Quinn N, Marsden CD, Parkes JD.  Complicated response fluctuations in 
Parkinson's disease:  response to intravenous infusion of levodopa.  Lancet.  
1982;2(8295):412-5.
10.
Quinn N, Parkes JD, Mardsen CD.  Control of on/off phenomenon by continuous 
intravenous infusion of levodopa.  Neurology.  1984;34(9):1131-6.


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11.
Deep-Brain Stimulation for Parkinson's Disease Study Group.  Deep-brain 
stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in 
Parkinson's disease.  N Engl J Med.  2001;345(13):956-63.
12.
Hariz MI.  Complications of deep brain stimulation surgery.  Mov Disord.  
2002;17(Suppl 3):S162-6.
13.
Nyholm D, Askmark H, Gomes-Trolin C, et al.  Optimizing levodopa 
pharmacokinetics:  intestinal infusion versus oral sustained release tablets.  Clin 
Neuropharmacol.  2003;26(3):156-63.
14.
AbbVie.  Levodopa-Carbidopa Intestinal Gel 20 mg/mL – 5 mg/mL.  Investigator 
Brochure Edition IB-187.07.  14 July 2011.
15.
Hauser RA, Friedlander J, Zesiewicz TA, et al.  A home diary to assess functional 
status in patients with Parkinson's disease with motor fluctuations and dyskinesia.  
Clin Neuropharmacol.  2000;23(2):75-81.
16.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs.columbia.edu/.


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Appendix A.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Research Manager Associate 
Clinical
Senior Director, Global Clinical Director
Clinical
Medical Director
Clinical
Associate Director
Statistics


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Appendix B.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
Contact:
 MD
Medical Director
Quintiles Medical & Scientific Services
10201 Wateridge Circle
San Diego, CA  92121
Office:
24 hour Urgent Medical 
Contact: +1 973-659-6677
 MD
Medical Advisor
Quintiles Medical & Scientific Services
Neurology, CNS, Therapeutic Delivery Unit
Sredniy prospect 36/40 
Letter 'K'
Commerce Center "Gustav" 7 floor
199004 Saint Petersburg
Russia
Office:
24 hour Urgent Medical 
Contact:
+1 973-659-6677
Has been changed to read:
Sponsor/Emergency 
Contact:
 MD
Medical Director
Quintiles Medical & Scientific Services
San Diego, CA  92121
Office:
24 hour Urgent Medical 
Contact: +1 973-659-6677 or
+1 570-819-8565 
(alternate number)
, MD
Medical Advisor
Quintiles Medical & Scientific Services
Neurology, CNS, Therapeutic Delivery Unit
Sredniy prospect 36/40 
Letter 'K'
Commerce Center "Gustav" 7 floor
199004 Saint Petersburg
Russia
Office:
24 hour Urgent Medical 
Contact: +1 973-659-6677 or
+1 570-819-8565 
(alternate number)


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Section 1.2  Synopsis
Previously read:
Name of Sponsor:  AbbVie
Protocol Number:  S187.3.005
Name of Finished Product:  Levodopa-Carbidopa 
Intestinal Gel (LCIG) 20 mg/mL - 5 mg/mL
Phase of Development:  3
Name of Active Ingredient:  Levodopa-Carbidopa
Date of Protocol Synopsis:  11 September 2013
Protocol Title:
Open-Label Continuation Treatment Study with Levodopa-Carbidopa Intestinal Gel in Subjects with 
Advanced Parkinson's Disease and Severe Motor-Fluctuations Who Have Exhibited a Persistent and 
Positive Effect to Treatment in Previous Studies
Study Center(s) (Planned):
Approximately 70
Study Duration:
The protocol duration is planned until the finished product is available commercially in the respective 
countries where subjects are participating in the study.  The expected protocol duration will continue 
through successful NDA and subsequent approval (approximately 4 years).  The protocol duration will 
be extended 4 years in the UK from the approval date of Amendment 3.01.  If it is deemed necessary to 
continue treatment after 4 years in the UK, either an amendment will be made to the current protocol 
or a new protocol will be submitted.
Objectives:
The primary objective is to provide continued access to subjects who would like to continue 
Levodopa-Carbidopa Intestinal Gel (LCIG), after completion of an open-label study (S187.3.003, 
S187.3.004, or any new Phase 3 open-label LCIG study initiated by the Sponsor).
Methodology:
This is a Phase 3B, open-label, multi-center, study.  Subjects will be provided with LCIG, if judged 
medically indicated and if it is not commercially available.  Data collected will be limited to the 
continued safety monitoring of LCIG with periodic assessment of the continued appropriateness of the 
subject's participation in the study.
Number of Subjects (Planned):
It is anticipated that approximately 275 subjects who had participated and completed one of the 
open-label LCIG clinical trials will be eligible for this continued treatment with LCIG, until it is 
commercially available.


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Diagnosis and Main Criteria for Inclusion:
In order to be eligible to participate in this study, subjects must meet the following criteria:
1. The subject should have completed participation in Study S187.3.003, S187.3.004, or any new 
Phase 3 open-label LCIG study initiated by the Sponsor; and, in the opinion of the Principal 
Investigator, would benefit from long-term treatment with LCIG.  For Canada, subjects will be 
allowed to participate in the S187.3.005 study with a minimum of 6 months of exposure to LCIG in 
the S187.3.004 study.
2. The subject must be able to understand the nature of the study and must provide written informed 
consent prior to the conduct of any study related procedures.
Main Criteria for Exclusion:
Subjects meeting any of the exclusion criteria listed below at Baseline must be excluded from 
participation in the study. 
1. Medical, laboratory, psychiatric, or surgical issues deemed by the Investigator to be clinically 
significant, and which could interfere with the subject's participation in the study.
Investigational Product, Dose and Mode of Administration:
LCIG is a homogenous suspension of levodopa (20 mg/mL) and carbidopa monohydrate (5 mg/mL) in an 
aqueous intestinal gel (carboxymethylcellulose).  LCIG (levodopa [20 mg/mL] and carbidopa 
monohydrate [5 mg/mL]) is delivered to the proximal small intestine through a jejunal extension tube 
inserted via percutaneous endoscopic gastrostomy (PEG-J).  The intestinal gel is dispensed in a 
medication cassette reservoir of 100 mL, designed to be connected to a portable subject-operated pump.  
LCIG infusion is administered over a full 16-hour period.  The gel will be administered as one morning 
dose, followed by continuous infusion for the remainder of the 16-hour period.  In addition to the 
morning dose and the continuous infusion, subjects will be allowed to self-administer additional doses of 
LCIG to address immediate subjective needs, such as the deterioration of motor function.  It is 
recommended that no more than five extra doses are given per day.  If subjects find it necessary to 
self-administer an increasing number of extra doses (> five/day) of LCIG, they will be instructed to 
contact their physician for appropriate follow-up care (adjustment of continuous infusion) as needed.  At 
night, after disconnecting the pump, the tubing is flushed with potable water.
Duration of Treatment:
In countries where LCIG is not commercially available, the treatment will be made available to subjects 
who complete participation in either LCIG open-label Study S187.3.003 or S187.3.004, or any new 
Phase 3 open-label LCIG study initiated by the Sponsor.  Such product will be made available by the 
Sponsor in accordance with all local regulations as long as such is warranted by the therapeutic benefit.  
The latter will be determined in consultancy with the responsible neurologist, the subject and the 
Sponsor.  Subjects who continue to receive drug will be evaluated at least semi-annually by the 
Investigator.  In cooperation with the investigational site, all necessary support will be provided by the 
Sponsor's local representatives.
Reference Therapy, Dose and Mode of Administration:
Not applicable.


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Criteria for Evaluation:
Safety and Tolerability Assessments:
Safety will be assessed by:

Physical examination, including weight

Neurological examination

Vital signs

Resting ECGs

C-SSRS

Clinical laboratory assessments including biochemistry, hematology,  urinalysis, and special labs 
to monitor for vitamin deficiencies

Concomitant medication usage

Adverse event monitoring (including sleep attacks, development of impulsive behavior and of 
melanoma)

Monitoring complications of the infusion device
Tolerability will be assessed by the number of subjects who complete the study.
Efficacy Assessments (for the subject's continuity in the study):

Periodic assessment of the appropriateness for continuation in the study

The decision to continue is based on the Principal Investigator's clinical judgment
Statistical Methods:
The primary statistical objective of this study will be to evaluate the long-term safety of LCIG.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of study medication in this 
study.  The Safety Population will be used for all analyses unless noted otherwise.
This is an open-label study with a single, active treatment group; all subjects in this study will receive 
LCIG.
Safety:
The safety population will be used for the analysis of the safety and tolerability data.
Safety will be evaluated using adverse events (AEs), complications of the infusion device, and changes in 
laboratory parameters, electrocardiograms, vital signs, C-SSRS and the Minnesota Impulsive Disorders 
Interview (MIDI).
Efficacy:
Not applicable.


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Has been changed to read:
Name of Sponsor:  AbbVie
Protocol Number:  S187.3.005
Name of Finished Product:  Levodopa-Carbidopa 
Intestinal Gel (LCIG) 20 mg/mL - 5 mg/mL
Phase of Development:  3
Name of Active Ingredient:  Levodopa-Carbidopa
Date of Protocol Synopsis:  17 December 2013
Protocol Title:
Open-Label Continuation Treatment Study with Levodopa-Carbidopa Intestinal Gel in Subjects with 
Advanced Parkinson's Disease and Severe Motor-Fluctuations Who Have Exhibited a Persistent and 
Positive Effect to Treatment in Previous Studies
Study Center(s) (Planned):
Approximately 70
Study Duration:
The protocol duration is planned until the finished product is available commercially in the respective 
countries where subjects are participating in the study.  The expected protocol duration will continue 
through successful NDA and subsequent approval (approximately 4 years).  The protocol duration will 
be extended 4 years in the UK from the approval date of Amendment 3.01.  If it is deemed necessary to 
continue treatment after 4 years in the UK, either an amendment will be made to the current protocol 
or a new protocol will be submitted.
Objectives:
The primary objective is to provide continued access to subjects who would like to continue 
Levodopa-Carbidopa Intestinal Gel (LCIG), after completion of an open-label study (S187.3.003 or 
S187.3.004).
The secondary objectives are to assess the long-term safety and tolerability of the LCIG therapeutic 
system, and to assess the maintenance of efficacy using data collected from US subjects.
Methodology:
This is a Phase 3B, open-label, multi-center, study.  Subjects will be provided with LCIG, if judged 
medically indicated and if it is not commercially available.  Data collected will be for evaluation of safety 
and efficacy, and for periodic assessment of the continued appropriateness of the subject's participation in 
the study.  The decision to continue is based on the Principal Investigator's clinical judgment.
Number of Subjects (Planned):
It is anticipated that approximately 275 subjects who had participated and completed one of the 
open-label LCIG clinical trials will be eligible for this continued treatment with LCIG, until it is 
commercially available.


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Diagnosis and Main Criteria for Inclusion:
In order to be eligible to participate in this study, subjects must meet the following criteria:
1. The subject should have completed participation in Study S187.3.003 or S187.3.004; and, in the 
opinion of the Principal Investigator, would benefit from long-term treatment with LCIG.  For 
Canada, subjects will be allowed to participate in the S187.3.005 study with a minimum of 
6 months of exposure to LCIG in the S187.3.004 study.
2. The subject must be able to understand the nature of the study and must provide written informed 
consent prior to the conduct of any study related procedures.  If the subject does not have the 
capacity to provide informed consent, full informed consent must be obtained from the subject's 
legally authorized representative.  Consenting will be performed according to local regulations.
Main Criteria for Exclusion:
Subjects meeting any of the exclusion criteria listed below at Baseline must be excluded from 
participation in the study. 
1. Medical, laboratory, psychiatric, or surgical issues deemed by the Investigator to be clinically 
significant, and which could interfere with the subject's participation in the study.
Investigational Product, Dose and Mode of Administration:
LCIG is a homogenous suspension of levodopa (20 mg/mL) and carbidopa monohydrate (5 mg/mL) in an 
aqueous intestinal gel (carboxymethylcellulose).  LCIG (levodopa [20 mg/mL] and carbidopa 
monohydrate [5 mg/mL]) is delivered to the proximal small intestine through a jejunal extension tube 
inserted via percutaneous endoscopic gastrostomy (PEG-J).  The intestinal gel is dispensed in a 
medication cassette reservoir of 100 mL, designed to be connected to a portable subject-operated pump.  
LCIG infusion is administered over a full 16-hour period.  The gel will be administered as one morning 
dose, followed by continuous infusion for the remainder of the 16-hour period.  In addition to the 
morning dose and the continuous infusion, subjects will be allowed to self-administer additional doses of 
LCIG to address immediate subjective needs, such as the deterioration of motor function.  It is 
recommended that no more than five extra doses are given per day.  If subjects find it necessary to 
self-administer an increasing number of extra doses (> five/day) of LCIG, they will be instructed to 
contact their physician for appropriate follow-up care (adjustment of continuous infusion) as needed.  At 
night, after disconnecting the pump, the tubing is flushed with potable water.
Duration of Treatment:
In countries where LCIG is not commercially available, the treatment will be made available to subjects 
who complete participation in either LCIG open-label Study S187.3.003 or S187.3.004.  Such product 
will be made available by the Sponsor in accordance with all local regulations as long as such is 
warranted by the therapeutic benefit.  The latter will be determined in consultancy with the responsible 
neurologist, the subject and the Sponsor.  Subjects who continue to receive study drug will be evaluated 
at least semi-annually by the Investigator.  In cooperation with the investigational site, all necessary 
support will be provided by the Sponsor's local representatives.
Reference Therapy, Dose and Mode of Administration:
Not applicable.


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Criteria for Evaluation:
Safety and Tolerability Assessments:
Safety will be assessed by:

Physical examination, including weight

Neurological examination

Vital signs

Resting ECGs

C-SSRS

Clinical laboratory assessments including biochemistry, hematology,  urinalysis, and special labs 
to monitor for vitamin deficiencies

Concomitant medication usage

Adverse event monitoring (including sleep attacks, development of impulsive behavior and of 
melanoma)

Monitoring complications of the infusion device
Tolerability will be assessed by the number of subjects who complete the study.
Efficacy Assessments at US Sites Only:

Parkinson's Disease Diary© assessment of motor state completed for the 3 consecutive days prior 
to each clinic visit

The Unified Parkinson's Disease Rating Scale (UPDRS)

Parkinson's Disease Questionnaire-39 (PDQ-39)
Statistical Methods:
The primary statistical objective of this study will be to evaluate the long-term safety of LCIG.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of study medication in this 
study.
Efficacy Population:
The Efficacy Population includes all subjects at US sites who have taken at least one dose of study 
medication in this study and have at least one efficacy assessment in this study.  
Safety:
The safety population will be used for the analysis of the safety and tolerability data.
Safety will be evaluated using adverse events (AEs), complications of the infusion device, and changes in 
laboratory parameters, electrocardiograms, vital signs, C-SSRS and the Minnesota Impulsive Disorders 
Interview (MIDI).


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Statistical Methods (Continued):
Efficacy:
The Efficacy Population will be used for the analysis of the efficacy data.
The mean change from baseline will be summarized for the following endpoints:

Off time, On time with troublesome dyskinesia, and On time without troublesome dyskinesia as 
measured by the Parkinson's Disease Diary

UPDRS total score, Parts I, II, II and IV scores, and dyskinesia item score

PDQ-39 summary index and domain scores
For the analysis of change from baseline in efficacy measures, each subject's baseline will be their 
baseline measure in the first LCIG study in which they participated (e.g., Study S187.3.001, 
Study S187.3.002 or Study S187.3.004).
Section 3.0  List of Abbreviations and Definition of Terms
Add:  three new abbreviations
CDA  ClinPhone Drug Accountability
PDQ-39  Parkinson's Disease Questionnaire
UPDRS  Unified Parkinson's Disease Rating Scale
Section 4.3  Subject Information and Consent
Second paragraph previously read:
The IEC/IRB approved informed consent form will be signed and personally dated by the 
subject (and if appropriate, their caregiver) and the person who conducted the informed 
consent discussion.  Each subject is to receive a copy of the signed and dated written 
informed consent form and any other written subject information.
Has been changed to read:
The IEC/IRB approved informed consent form will be signed and personally dated by the 
subject (and if appropriate, their caregiver) and the person who conducted the informed
consent discussion.  If the subject does not have the capacity to provide informed consent, 
full informed consent must be obtained from the subject's legally authorized 
representative.  Consenting will be performed according to local regulations.  Each 
subject is to receive a copy of the signed and dated written informed consent form and any 
other written subject information.


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Section 5.0  Introduction
Eleventh paragraph previously read:
This open-label, multi-center, Phase 3B study will provide continued treatment with 
LCIG to subjects who have already participated in an open-label treatment study with the 
same treatment (S187.3.003 or S187.3.004, or any new Phase 3 open-label LCIG study 
initiated by the Sponsor).  In countries where LCIG is not yet available commercially, the 
treatment will be made available by the Sponsor in accordance with all local regulations 
as long as such is warranted by the therapeutic benefit.  The latter will be determined in 
consultancy with the responsible neurologist, the subject and the Sponsor.  Subjects who 
continue to receive drug will be evaluated at least semi-annually by the Investigator.  In 
cooperation with the investigational site, all necessary support will be provided by the 
Sponsor's local representatives.  Additionally, the study will allow for observation of the 
long-term safety and tolerability of LCIG administered for several years in a more 
naturalistic treatment environment.
Has been changed to read:
This open-label, multi-center, Phase 3B study will provide continued treatment with 
LCIG to subjects who have already participated in an open-label treatment study with the 
same treatment (S187.3.003 or S187.3.004).  In countries where LCIG is not yet available 
commercially, the treatment will be made available by the Sponsor in accordance with all 
local regulations as long as such is warranted by the therapeutic benefit.  The latter will be 
determined in consultancy with the responsible neurologist, the subject and the Sponsor.  
Subjects who continue to receive study drug will be evaluated at least semi-annually by 
the Investigator.  In cooperation with the investigational site, all necessary support will be 
provided by the Sponsor's local representatives.  Additionally, the study will allow for 
observation of the long-term safety, tolerability, and maintenance of efficacy of LCIG 
administered for several years in a more naturalistic treatment environment.


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Section 6.1  Primary Objective
Previously read:
The primary objective of this study is to provide, under well-controlled conditions, 
continued access to LCIG treatment to subjects who have already participated in an 
open-label efficacy and safety trial with the same treatment (S187.3.003, S187.3.004, or 
any new Phase 3 open-label LCIG study initiated by the Sponsor), and in whom the need 
for such continuation is indicated, as confirmed by periodic evaluation, until the product is 
commercially available.
Has been changed to read:
The primary objective of this study is to provide, under well-controlled conditions, 
continued access to LCIG treatment to subjects who have already participated in an 
open-label efficacy and safety trial with the same treatment (Study S187.3.003 or 
S187.3.004), and in whom the need for such continuation is indicated, as confirmed by 
periodic evaluation, until the product is commercially available.
Section 6.2  Safety Objectives
Section title and text previously read:
6.2
Safety Objectives
To assess the long-term safety and tolerability of the LCIG therapeutic system by the 
following:
●
Physical examination, including weight
●
Neurological examination
●
Vital signs
●
Resting ECGs
●
Columbia Suicide-Severity Rating Scale (C-SSRS)
●
Clinical laboratory assessments including biochemistry, hematology, 
urinalysis, and special labs to monitor for vitamin deficiencies
●
Concomitant medication usage


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●
Adverse event monitoring, including for the development of sleep attacks,  
melanoma, or excessive impulsive behavior
●
Monitoring complications of the infusion device
●
Tolerability assessed by number of subjects who complete the study
Has been changed to read:
6.2
Secondary Objectives
To assess the long-term safety and tolerability of the LCIG therapeutic system, and to 
assess the maintenance of efficacy using data collected from US subjects.
Safety and tolerability will be assessed by the following:
●
Physical examination, including weight
●
Neurological examination
●
Vital signs
●
Resting ECGs
●
Columbia Suicide-Severity Rating Scale (C-SSRS)
●
Clinical laboratory assessments including biochemistry, hematology, 
urinalysis, and special labs to monitor for vitamin deficiencies
●
Concomitant medication usage
●
Adverse event monitoring, including for the development of sleep attacks,  
melanoma, or excessive impulsive behavior
●
Monitoring complications of the infusion device
●
Tolerability assessed by number of subjects who complete the study
Maintenance of efficacy will be assessed by evaluating the mean change from baseline in 
the following:
●
Off time, On time with troublesome dyskinesia and On time without 
troublesome dyskinesia as measured by the Parkinson's Disease Diary


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●
UPDRS total score, Parts I, II, III and IV scores, and dyskinesia item score
●
PDQ-39 summary index and domain scores
For the analysis of change from baseline in efficacy measures, each subject's baseline will 
be their baseline measure in the first LCIG study in which they participated 
(e.g., Study S187.3.001, S187.3.002 or S187.3.004).
Section 7.1  Overall Study Design and Plan Description
First and second paragraphs previously read:
This is a Phase 3B, open-label, multi-center study of the long-term safety and tolerability 
of LCIG in the continuation of treatment of approximately 275 advanced Parkinson's 
disease subjects with a good therapeutic response on LCIG with regard to the treatment of 
persistent severe motor fluctuations.  The study will be conducted at approximately 
70 centers.
Only subjects who have completed Study S187.3.003, S187.3.004, or any new Phase 3 
open-label LCIG study initiated by the Sponsor, will qualify for enrollment in this study.  
Following informed consent, subjects will have their inclusion/exclusion criteria assessed 
prior to beginning treatment in this study.  Subjects are allowed to have a caregiver, if 
appropriate, assist them with study requirements, i.e., care of the pump and tubing, etc. 
and the caregiver will have been trained accordingly.
Has been changed to read:
This is a Phase 3B, open-label, multi-center study of the long-term safety and tolerability 
of LCIG in the continuation of treatment of approximately 275 advanced Parkinson's 
disease subjects with a good therapeutic response on LCIG with regard to the treatment of 
persistent severe motor fluctuations.  The study will be conducted at approximately 
70 centers.  In addition, maintenance of efficacy will be evaluated at approximately 28 US 
sites.


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Only subjects who have completed Study S187.3.003 or S187.3.004 will qualify for 
enrollment in this study.  Following informed consent, subjects will have their 
inclusion/exclusion criteria assessed prior to beginning treatment in this study.  Subjects 
are allowed to have a caregiver, if appropriate, assist them with study requirements, 
i.e., care of the pump and tubing, etc. and the caregiver will have been trained 
accordingly.
Section 7.1  Overall Study Design and Plan Description
Add:  new ninth paragraph and bullets
The following efficacy assessments will be completed at US sites: 
●
Parkinson's Disease Diary© assessment of motor state completed for the 
3 consecutive days prior to each clinic visit (excluding the drug dispensation 
visits),
●
Unified Parkinson's Disease Rating Scale (UPDRS), and 
●
Parkinson's Disease Questionnaire-39 (PDQ-39).
Section 7.2  Discussion of Study Design, Including the Choice of Control Groups
Previously read:
This study is an open-label continuation treatment study and all subjects will receive 
open-label LCIG therapy.  In order to be enrolled in this study subjects will need to 
complete Study S187.3.003, S187.3.004, or any new Phase 3 open-label LCIG study 
initiated by the Sponsor.
Has been changed to read:
This study is an open-label continuation treatment study and all subjects will receive 
open-label LCIG therapy.  In order to be enrolled in this study subjects will need to 
complete Study S187.3.003 or S187.3.004.


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Section 8.1  Inclusion Criteria
Previously read:
In order to be eligible to participate in this study, subjects must meet the following 
criteria:
1.
The subject should have completed participation in Study S187.3.003, S187.3.004, 
or any new Phase 3 open-label LCIG study initiated by the Sponsor; and, in the
opinion of the Principal Investigator, would benefit from long-term treatment with 
LCIG.  For Canada, subjects will be allowed to participate in the S187.3.005 study 
with a minimum of 6 months of exposure to LCIG in the S187.3.004 study.
2.
The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study related procedures.
Has been changed to read:
In order to be eligible to participate in this study, subjects must meet the following 
criteria:
1.
The subject should have completed participation in Study S187.3.003 or 
S187.3.004; and, in the opinion of the Principal Investigator, would benefit from 
long-term treatment with LCIG.  For Canada, subjects will be allowed to 
participate in the S187.3.005 study with a minimum of 6 months of exposure to 
LCIG in the S187.3.004 study.
2.
The subject must be able to understand the nature of the study and must provide 
written informed consent prior to the conduct of any study related procedures.  If 
the subject does not have the capacity to provide informed consent, full informed 
consent must be obtained from the subject's legally authorized representative.  
Consenting will be performed according to local regulations.


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Section 10.3  Ordering, Storage and Dispensing of Medication and Device
Second and third paragraphs previously read:
All clinical devices (e.g., pumps and tubing) are to be stored in a secure, limited-access 
area in accordance with labeled storage conditions.  The Investigator will maintain 
accurate records of the receipt and disposition of all clinical device supplies received 
during the study.  These records shall include the number of clinical devices and the dates 
on which devices were received from the Sponsor (or an authorized representative), 
dispensed to the subject, returned by the subject and returned to the Sponsor (or an 
authorized representative).  If errors or damages in the clinical device shipments occur, 
the Investigator must contact the Sponsor (or an authorized representative) immediately.
Subjects will receive study medication at the Baseline visits, and regular 6 month clinical 
visits.  In addition, subjects do need to come into the clinic for clinical supply visits at the 
pharmacy every 6 weeks (± 7 days), so that there is no risk of medication expiring.  When 
scheduling the 6 weekly drug dispensing visits, the site should always refer back to the 
baseline visit.  Every attempt should be made to bring the subject back on the original 
targeted dates (±7 days).
Has been changed to read:
All clinical devices (e.g., pumps and tubing) are to be stored in a secure, limited-access 
area.  The Investigator will maintain accurate records of the receipt and disposition of all 
clinical device supplies received during the study.  These records shall include the number 
of clinical devices and the dates on which devices were received from the Sponsor (or an 
authorized representative), dispensed to the subject, returned by the subject and returned 
to the Sponsor (or an authorized representative).  If errors or damages in the clinical 
device shipments occur, the Investigator must contact the Sponsor (or an authorized 
representative) immediately.
Subjects will receive study medication at the Baseline visits, and regular 6 month clinical 
visits.  In addition, subjects do need to come into the clinic or pharmacy for clinical 
supply visits every 6 weeks (± 7 days), so that there is no risk of medication expiring.  


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Other assessments may be completed during these visits if required.  When scheduling the 
6 weekly drug dispensing visits, the site should always refer back to the baseline visit.  
Every attempt should be made to bring the subject back on the original targeted dates 
(±7 days).
Section 10.9  Treatment Compliance
Previously read:
The Investigator (or designee) must document the amount of study drug dispensed to the 
subject and returned from the subject on the provided Drug Accountability Form and 
eCRF.  In case of discrepancies in the actual amount of study drug returned versus what 
should have been returned, the subject will provide the Investigator (or designee) with an 
explanation, and the explanation must be recorded on the Drug Accountability form.
Drug Accountability
The Investigator is accountable for all clinical drug supplies shipped to his/her study site 
for the duration of the study.  Activities relating to drug accountability may be performed 
by a pharmacist as designated by the Investigator.  A final accounting of the clinical drug 
supplies will be required at the completion/termination of the study.  The Investigator is 
required to provide written explanation for any discrepancies.  All unused clinical drug 
supplies (except required retention samples) and packaging materials will be inventoried 
and returned to the Sponsor (or an authorized representative) by a designated monitor.  
The Investigator will not be permitted to return or destroy unused clinical drug supplies or 
packaging materials unless authorized by the Sponsor (or authorized representative).
Device Accountability
The Investigator is accountable for all investigative devices (e.g., pumps, tubing) that 
were shipped to his/her site for use in the study.  All unused clinical devices and 
packaging materials will be inventoried and returned to the Sponsor (or an authorized 
representative) by designated personnel.  The Investigator will not be permitted to return 


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or destroy unused clinical devices or packaging materials unless authorized by the 
Sponsor (or authorized representative).
Has been changed to read:
The Investigator (or designee) must document the amount of study drug dispensed to the 
subject and returned from the subject in the ClinPhone Drug Accountability (CDA) 
System and on the eCRF.  In case of discrepancies in the actual amount of study drug 
returned versus what should have been returned, the subject will provide the Investigator 
(or designee) with an explanation, and the explanation must be recorded in the CDA 
system and in the source notes.
Drug Accountability
The Investigator (or designee) is accountable for all clinical drug supplies shipped to 
his/her study site for the duration of the study.  Previously completed paper drug 
accountability logs will not be completed anymore, but need to be kept on-site in the 
investigator site file for further reference.  An overall accountability of the study drug will 
be performed and verified by the site and designated monitor throughout the study and at 
the site close-out visit.  After verification of drug accountability using the CDA system, 
all clinical drug supplies must be inventoried, accounted for and returned to the drug 
destruction depot.  A final accounting of the clinical drug supplies will be required at the 
completion/termination of the study.  The Investigator (or designee) is required to provide 
written explanation for any discrepancies.  All used and unused clinical drug supplies will 
be inventoried and returned to the Sponsor (or an authorized representative) by the site or 
by a designated monitor.
Device Accountability
The Investigator (or designee) is accountable for all investigative devices (e.g., pumps, 
tubing) that were shipped to his/her site for use in the study (ancillary supplies).  
Previously completed paper accountability logs for ancillary supplies will not be 
completed anymore, but need to be kept on-site in the investigator site file for further 


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reference.  An overall accountability of the ancillary supplies will be performed and 
verified by the site and monitor throughout the study and at the site close-out visit.  After 
verification of device accountability using the CDA system, used or expired unused 
devices, with the exclusion of pumps, will be discarded per the site's institutional policy, 
unless it has been requested to be returned for investigation.  If a device (i.e., tubing, 
cassette, pump) is requested to be returned for further investigation, instructions will be 
provided.  All pumps will be returned using instructions provided.
Section 11.0  Study Assessments (Criteria for Evaluation) and Flow Chart
Add:  second paragraph
In the event a study subject transfers to LCIG commercial product, all assessments under 
termination assessments in the Flow Chart of Assessments must be completed prior to 
transferring to commercial product, with the exception of the removal of the PEG tube 
which will remain in place.
Section 11.2  Efficacy Measurements
Previously read:
Not applicable.
Has been changed to read:
Efficacy will be assessed using the Parkinson's Disease Diary©, UPDRS, and the PDQ-39.
Appropriate study site personnel must be trained on the use of all scales used in this study.
Section 11.2.1  Parkinson's Disease Diary (Symptom Diary)
Add:  section title and text
11.2.1
Parkinson's Disease Diary (Symptom Diary)
The core of the Parkinson's Disease Diary (PD Diary) is the tool that the subject will use 
to record Parkinsonian symptoms.  The subject and/or caregiver will be prompted to 
answer the PD Diary whether the subject has been "ON," "OFF," or "ASLEEP" and what 
has been the severity of the dyskinesias (troublesome or not troublesome).  On PD Diary 


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recording days, subjects will be instructed to make an entry upon waking and every 
30 minutes during their normal waking time.
Study site staff should make a call to the subjects in advance of their clinic visit to review 
with them the need to complete the PD Diary for the visit.
The PD Diary is to be recorded at the times indicated in Table 2.
Subject Training Requirements
During the initial LCIG study the subject and caregiver, if applicable, were required to 
have diary training which included training of how to understand PD symptomatology and 
how to complete the PD Diary.  A refresher training will be provided to the subjects and 
their caregivers.
Site personnel should emphasize the importance of completing the PD Diary at half-hour 
time points in real time during waking hours to ensure true evaluation of the subject's 
condition.
Section 11.2.2  UPDRS
Add:  new section title and text
11.2.2
UPDRS
The United Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool 
to follow the longitudinal course of Parkinson's disease.  To be qualified by the Sponsor, 
all raters must have participated in the Rater Training and have a current valid Rater 
Certificate.  The UPDRS is made up of the following sections:
●
Part I – Mentation, Behavior, and Mood
●
Part II – Activities of Daily Living
●
Part III – Motor Examination
●
Part IV – Complications of Therapy (including dyskinesias)


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●
Part V – Modified Hoehn and Yahr Staging
●
Part VI – Schwab and England Activities of Daily Living Scale
Some sections require multiple grades assigned to each extremity.  UPDRS total score 
ranges from 0 to 176, with 176 representing the worst (total) disability, and 0 no 
disability.  Additionally, Questions 32, 33, and 34 on UPDRS will be totaled to evaluate 
dyskinesias.  
The complete UPDRS (all sections) should be completed at the times indicated in Table 2.
The complete UPDRS will be done within 1 to 4 hours after the first morning dose of trial 
medication during LCIG treatment.  
UPDRS Rater Training
The UPDRS assessments will be administered only by individuals qualified by the 
Sponsor and rater training vendor.  
Prior to administration of respective scale(s), designated raters (Investigator or an 
experienced and medically qualified study site designee (e.g., RN, NP, PA, DO, MD, or 
PhD) assigned by the Investigator) must be certified in the use of the UPDRS.  The 
objective of this certification/training is to ensure uniformity across sites in the 
administration and scoring of these assessments. 
AbbVie, in conjunction with the rater training vendor, will determine the minimum rater 
qualifications for the rating scales.  All raters must meet these qualifications prior to 
participation in the training process.  The qualifications of the raters will be verified 
through the training vendor.  Qualified raters will be certified or re-certified based on 
prior LCIG study training.  Individual exceptions to these requirements must be approved 
by the Sponsor via the training vendor.
Only those persons who have been trained and certified as raters for this study may rate 
the subjects.  Raters who become involved in the study after the initial training will not be 


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permitted to perform study ratings until they have satisfactorily completed an 
individualized training program designed by the rater training vendor, approved by 
AbbVie, and supervised by the Investigator or his/her designee.  Raters may be reassessed 
periodically throughout the study.
Section 11.2.3  PDQ-39
Add:  new section title and text
11.2.3
PDQ-39
The Parkinson's Disease Questionnaire (PDQ-39) is a disease-specific instrument 
designed to measure aspects of health that are relevant to subjects with PD, and which 
may not be included in general health status questionnaires.  The PDQ-39 is a 
self-administered questionnaire that comprises 39 items addressing the following 
eight domains of health that subjects consider to be adversely affected by the disease:
●
Mobility (e.g., fear of falling when walking)
●
Activities of daily living (e.g., difficulty cutting food)
●
Emotional well-being (e.g., feelings of isolation)
●
Stigma (e.g., social embarrassment)
●
Social support
●
Cognition
●
Communication
●
Bodily discomfort
The PDQ-39 summary index ranges from 0 to 100, where lower scores indicate a better 
perceived health status.  Higher scores are consistently associated with the more severe 
symptoms of the disease such as tremor and stiffness.  In addition to the summary index, 
the results can be presented as eight discrete domain scores.  The PDQ-39 will be 
completed at the times indicated in Table 2.


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Section 11.3  Other Assessments
Previously read:
Informed Consent
Voluntary written informed consent must be obtained from each subject (and if 
appropriate, their caregiver) prior to performing any study-related procedures (see 
Section 4.3).
Concomitant Medication
Concomitant medication will be recorded at each study visit.  All medication taken by the 
subject during the study (from signing the Informed Consent form through post-study 
follow-up) is to be recorded on the Concomitant Medication eCRF form, except for study 
drug.
Determination of Continued Benefit
A standard neurological exam should be performed every 6 months to evaluate the 
subject's condition.  The decision to continue on LCIG treatment is based on the Principal 
Investigator's clinical judgment.
Has been changed to read:
Informed Consent
Voluntary written informed consent must be obtained from each subject (and if 
appropriate, their caregiver) prior to performing any study-related procedures (see 
Section 4.3).  If the subject does not have the capacity to provide informed consent, full 
informed consent must be obtained from the subject's legally authorized representative.  
Consenting will be performed according to local regulations.


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Concomitant Medication
Concomitant medication will be recorded at each study visit.  All medication taken by the 
subject during the study (from signing the Informed Consent form through post-study 
follow-up) is to be recorded on the Concomitant Medication eCRF form, except for study 
drug.
Determination of Continued Benefit
A standard neurological exam should be performed every 6 months to evaluate the 
subject's condition.  The decision to continue on LCIG treatment is based on the Principal 
Investigator's clinical judgment.
Daily Dosing Diary (US sites only)
Subjects will complete a Daily Dosing Diary on the days indicated in Table 2.  The diary 
will include the date and actual clock time of all levodopa-carbidopa intestinal gel 
infusions (including pump start time, pump stop time and the time of any extra dose 
administration) and all oral levodopa/carbidopa doses.
Study site staff should make a call to the subjects in advance of their clinic visit to review 
with them the need to complete the Daily Dosing Diary for the visit.
The subject or a caregiver should complete a Daily Dosing Diary for study drug 
administration on the days indicated in Table 2.
Section 11.4  Appropriateness of Measurements
Previously read:
Not applicable.


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Has been changed to read:
The PD Diary, UPDRS, and PDQ-39 are currently accepted and validated methods of 
evaluating subjects with PD. All safety assessments are standard measures used in 
pharmaceutical research.


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Table 2.  Flow Chart of Study Assessments
Previously read:
Visit
Baseline
6 Monthly 
Visit
Termination
Follow-up*
Day
Final Assessment 
in Previous Study
+/– 14 Days
--
Termination Visit 
+ 7 Days
Informed consent
X
Inclusion/exclusion 
X
Physical exam
Xa
X
X
Neurological Exam
Xa
X
X
Weight
Xa
X
X
Vital signs
Xa
X
X
X
12-lead ECG
Xa
Xb
X
Clinical labs
Xa
Xb
X
Folic Acid, Vitamins B6, 
B12, Methylmalonic Acid 
(MMA), and 
Homocysteine Levels
Xa
X
X
β-HCGc
Xa
X
X
Adverse events
Xa
X
X
X
Concomitant medication
Xa
X
X
X
Sleep attacks
Xa
X
X
Melanoma check
Xa
Xd
X
Determination of 
continued benefit**
X
X
MIDI 
Xa
X
X
C-SSRSf
Xa
X
X
X
Complications with 
infusion device
Xa
X
X
Inspection of stoma
Xa
X
X
X
Assessment of the need to 
replace PEG-J***
X
Xd
Dispensing of study drug
X
Every 6 weekse
Removal of PEG****
X


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Table 2.
Flow Chart of Study Assessments (Continued)
*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug after 
termination.
**
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
*** On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice. 
****For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to 
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
f.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
g.
Will be done as clinically indicated.
h.
For women of childbearing potential.
i.
Assessment performed once yearly.
j.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits will take place at the hospital 
pharmacy and are for the sole purpose of dispensing clinical study drug and ancillary supplies.  When scheduling 
the 6 weekly drug dispensing visits, the site should always refer back to the baseline visit.  Every attempt should be 
made to bring the subject back on the original targeted dates (±7 days).
f.
The "Already Enrolled Subjects" C-SSRS is to be the first assessment scale administered to the subject.  At each 
subsequent assessment, the "Since Last Visit" C-SSRS scale should be administered.  If the subject has previously 
completed the "Already Enrolled Subjects" scale in the S187.3.003 study, the subject should complete the "Since 
Last Visit" scale at all scheduled time points outlined in Table 2 in this study.  For subjects with a C-SSRS 
completed at their S187.3.003 final visit, that S187.3.003 final visit C-SSRS assessment will be considered 
baseline for the S187.3.005 study.  For all other subjects, the first C-SSRS assessment completed in this study will 
serve as baseline.


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Has been changed to read:
Visit
Baseline
6 Monthly 
Visit
Termination/ 
Transfer to 
Commercial
Follow-up*
Day
Final Assessment 
in Previous Study
+/– 14 Days
--
Termination Visit 
+ 7 Days
Informed consent
X
Inclusion/exclusion 
X
Physical exam
Xa
X
X
Neurological Exam
Xa
X
X
Weight
Xa
X
X
Vital signs
Xa
X
X
X
12-lead ECG
Xa
Xb
X
Clinical labs
Xa
Xb
X
Folic Acid, Vitamins B6, 
B12, Methylmalonic Acid 
(MMA), and 
Homocysteine Levels
Xa
X
X
β-HCGc
Xa
X
X
Adverse events**
Xa-------------------------------------------------------------------X
Concomitant medication
Xa
X
X
X
Sleep attacks
Xa
X
X
Melanoma check
Xa
Xd
X
Determination of 
continued benefit***
X
X
MIDI 
Xa
X
X
C-SSRSf
Xa
X
X
X
Complications with 
infusion device
Xa
X
X
Inspection of stoma
Xa
X
X
X
Assessment of the need to 
replace PEG-J****
X
Xd
Dispensing of study drug
X-----Every 6 weekse-----
Daily Dosing Diaryg
X
X


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Table 2.
Flow Chart of Study Assessments (Continued)
Visit
Baseline
6 Monthly 
Visit
Termination/ 
Transfer to 
Commercial
Follow-up*
Parkinson's Disease Diaryg
X
X
UPDRSh
X
X
PDQ-39h
X
X
Removal of PEG*****
X
*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug 
after termination.
**
Collection of adverse events is an ongoing and continuous process, not only occurring during site visits.
***
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
****
On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice. 
***** For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to 
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
k.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
l.
Will be done as clinically indicated.
m.
For women of childbearing potential.
n.
Assessment performed once yearly.
o.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits may take place at the hospital 
pharmacy and are for the purpose of dispensing clinical study drug and ancillary supplies.  Other assessments may 
be completed during these visits if required.  When scheduling the 6 weekly drug dispensing visits, the site should 
always refer back to the baseline visit.  Every attempt should be made to pick up drug on the original targeted dates 
(±7 days).
f.
The "Already Enrolled Subjects" C-SSRS is to be the first assessment scale administered to the subject.  At each 
subsequent assessment, the "Since Last Visit" C-SSRS scale should be administered.  If the subject has previously 
completed the "Already Enrolled Subjects" scale in the S187.3.003 study, the subject should complete the "Since 
Last Visit" scale at all scheduled time points outlined in Table 2 in this study.  For subjects with a C-SSRS 
completed at their S187.3.003 final visit, that S187.3.003 final visit C-SSRS assessment will be considered 
baseline for the S187.3.005 study.  For all other subjects, the first C-SSRS assessment completed in this study will 
serve as baseline.
g.
The Daily Dosing Diary and the Parkinson's Disease Diary will be completed by subjects or their caregivers for the 
3 consecutive days prior to each clinic visit at US sites only.
h.
The UPDRS and the PDQ-39 will be completed at US sites only.


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Section 12.1.4  Adverse Events of Special Interest
Third paragraph previously read:
For serious gastrointestinal adverse events of special interest, severe infections in 
connection with the tubing system and cardiovascular fatalities, specific questionnaires 
will be used for standardized collection of follow-up information.
Has been changed to read:
For AESIs, serious and nonserious, meeting pre-defined criteria, specific questionnaires 
will be used to standardize the collection of follow-up information.
Section 13.2  Analysis Populations
First paragraph and numbered list previously read:
Definitions of analysis populations:
1.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of 
study medication in this study.  The Safety Population will be used for all analyses 
unless noted otherwise.
Has been changed to read:
Definitions of analysis populations:
1.
Safety Population:
The Safety Population includes all subjects who have taken at least one dose of 
study medication in this study.  The Safety Population will be used for all analyses 
unless noted otherwise.


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2.
Efficacy Population:
The Efficacy Population includes all subjects who have taken at least one dose of 
study medication in this study and have at least one efficacy assessment in this 
study.
Section 13.3  Statistical Methods
Previously read:
Safety Analysis
The Safety Population will be used for the analysis of the safety and tolerability data.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  A treatment-emergent adverse event (TEAE) is defined as any adverse event 
that begins or worsens in severity on or after the first dose of study drug in the current 
study and within 30 days of the last dose of study drug in the current study.  The 
following summaries of TEAE's will be prepared:
●
Incidence of treatment-emergent adverse events
●
Incidence of treatment-emergent serious adverse events
●
Incidence of treatment-emergent adverse events resulting in study termination
●
Incidence of treatment-emergent adverse events of special interest
The following additional analyses of safety will also be prepared:
●
Summary of vital sign and weight values and change from Baseline over time
●
Incidence of potentially clinically significant vital sign and weight values
●
Summary of clinical lab values and change from Baseline to Endpoint
●
Summary of special lab values and change from Baseline over time
●
Summary of ECG clinical interpretations over time
●
Shifts in ECG clinical interpretations from Baseline to Endpoint
●
Summary of neurological examination clinical interpretations over time


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●
Shifts in neurological examination clinical interpretations over time
●
Summary of MIDI at Baseline and during treatment
●
Summary of C-SSRS
●
Incidence of device complications
Additional Analysis
Subject disposition will be summarized including the primary reason for premature 
discontinuations and a listing of all subjects not included in the safety population.
Descriptive statistics will be provided for demographics and baseline characteristics.
Concomitant medication use will be summarized over time.
Baseline and Endpoint
The baseline value for a variable is defined as the last non-missing value collected in the 
current study or the previous open-label LCIG study before the first dose of study drug in 
the current study.
The endpoint value for a variable is defined as the last non-missing value assigned to the 
treatment for the subject.
Has been changed to read:
Safety Analysis
The Safety Population will be used for the analysis of the safety and tolerability data.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  A treatment-emergent adverse event (TEAE) is defined as any adverse event 
that begins or worsens in severity on or after the first dose of study drug in the current 
study and within 30 days of the end of LCIG treatment in the current study.  For subjects 
transferring to commercial product, the end of treatment in the current study will be the 


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last dose of study drug.  For subjects who are discontinuing LCIG treatment, the end of 
treatment in the current study will be the removal of the PEG-J tube.  The following 
summaries of TEAE's will be prepared:
●
Incidence of treatment-emergent adverse events
●
Incidence of treatment-emergent serious adverse events
●
Incidence of treatment-emergent adverse events resulting in study termination
●
Incidence of treatment-emergent adverse events of special interest
The following additional analyses of safety will also be prepared:
●
Summary of vital sign and weight values and mean change from Baseline over 
time
●
Incidence of potentially clinically significant vital sign and weight values
●
Summary of clinical lab values and mean change from Baseline to Endpoint
●
Summary of special lab values and mean change from Baseline over time
●
Incidence of potentially clinically significant clinical lab values
●
Summary of MIDI at Baseline and during treatment
●
Summary of C-SSRS
●
Incidence of device complications
Efficacy Analysis
The Efficacy Population will be used for analyses of efficacy.  The mean change from 
baseline to endpoint will be summarized for the following efficacy endpoints.
●
"Off" time as measured by the Parkinson's Disease Diary
●
"On" time without troublesome dyskinesia (sum of "On" time without 
dyskinesia and "On" time with non-troublesome dyskinesia) as measured by 
the Parkinson's Disease Diary
●
UPDRS total score, Parts I, II, III and IV scores, and dyskinesia item score
●
PDQ-39 summary index and domain scores


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For the analysis of change from baseline in efficacy measures, each subject's baseline will 
be their baseline measure in the first LCIG study in which they participated 
(e.g., Study S187.3.001, S187.3.002 or S187.3.004).
Additional Analysis
Subject disposition will be summarized including the primary reason for premature 
discontinuations and a listing of all subjects not included in the safety population.
Descriptive statistics will be provided for demographics and baseline characteristics.
Concomitant medication use will be summarized over time.
Baseline and Endpoint
Unless noted otherwise, the baseline value for a variable is defined as the last non-missing 
value collected in the current study or the previous open-label LCIG study before the 
first dose of study drug in the current study.
The endpoint value for a variable is defined as the last non-missing value assigned to the 
treatment period in the current study for the subject.  For subjects transferring to 
commercial product, the end of treatment in the current study will be the last dose of study 
drug.  For subjects who are discontinuing LCIG treatment, the end of treatment in the 
current study will be the removal of the PEG-J tube.
Section 13.5  Rationale for Alpha Test Tested
Section title and text previously read:
13.5
Rationale for Alpha Test Tested
Not applicable.


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Has been changed to read:
13.5
Sample Size
This is an open-label extension study.  All subjects in a country where LCIG is not 
commercially available will be eligible to enroll if they meet the study's inclusion criteria 
and exclusion criteria.
Section 13.6  Power Needed
Delete:  section title and text
13.6
Power Needed
Not applicable.
Section 13.7  Rationale for Power Needed
Delete:  section title and text
13.7
Rationale for Power Needed
Not applicable.
Section 13.8  Power Calculation, Assumptions and Basis for Assumptions
Delete:  section title and text
13.8
Power Calculation, Assumptions and Basis for 
Assumptions
Not applicable.
Appendix A.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Associate Medical Director
Clinical
Clinical Research Manager Associate 
Clinical
Senior Director, Global Clinical Director
Clinical
Associate Director
Statistics


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Has been changed to read:
Name
Title
Functional Area
Clinical Research Manager Associate 
Clinical
Senior Director, Global Clinical Director
Clinical
Medical Director
Clinical
Associate Director
Statistics

SAP_001.pdf: 
Levodopa-Carbidopa
S1873005 – Statistical Analysis Plan
Version 4.0 – 08 November 2016
1
1.0
Title Page
Statistical Analysis Plan
Study S187.3.005
Open-Label Continuation Treatment Study with 
Levodopa-Carbidopa Intestinal Gel in Subjects with 
Advanced Parkinson's Disease and Severe Motor 
Fluctuations Who Have Exhibited a Persistent and 
Positive Effect to Treatment in Previous Studies
08 November 2016
 
NCT00660673


Levodopa-Carbidopa
S1873005 – Statistical Analysis Plan
Version 4.0 – 08 November 2016
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Abbreviations and Definitions of Terms...............................6
4.0
Introduction .............................................................................9
5.0
Summary of the Protocol and Amendments.........................9
5.1
Study Schedule of Assessments.................................................................9
5.2
Overall Study Plan ...................................................................................10
5.3
Treatments................................................................................................12
5.4
Data Safety Monitoring Board.................................................................13
6.0
General Definitions, Methods, Naming Conventions 
and Data Handling ................................................................13
6.1
General Methodology and Presentation...................................................14
6.2
Treatment Group Names and Labels .......................................................14
6.3
Visit Names and Labels ...........................................................................15
6.4
Day Numbers, Study Periods and Visit Windows:  Related 
Definitions................................................................................................15
6.4.1
General Definitions..................................................................................15
6.4.2
Initial Screening Period............................................................................17
6.4.3
Initial PEG-J Placement...........................................................................17
6.4.4
Initial LCIG Infusion ...............................................................................18
6.4.5
Baseline Period for Study 3005 ...............................................................18
6.4.6
Treatment Period......................................................................................19
6.4.7
Post-Treatment Period .............................................................................19
6.4.8
Visit Windowing Conventions.................................................................20
6.4.9
3005 Treatment Year ...............................................................................21
6.5
Handling of Missing Data........................................................................21
7.0
Objectives ...............................................................................21
7.1
Primary Objective ....................................................................................21
7.2
Secondary Objectives...............................................................................22
8.0
Analysis Variables:  Definitions, Derivations, 
Calculations and Conventions..............................................23
 


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8.1
Subject Disposition ..................................................................................23
8.1.1
Subject Samples.......................................................................................23
8.1.2
Subgroups ................................................................................................24
8.1.3
Protocol Deviations..................................................................................24
8.1.4
Inclusion/Exclusion Criteria ....................................................................25
8.1.5
Subject Enrollment and Disposition ........................................................25
8.2
Subject Characteristics.............................................................................26
8.2.1
Demographic Data ...................................................................................26
8.2.2
Other Baseline Characteristics.................................................................27
8.2.3
Medical History and Other Disease History ............................................28
8.2.3.1
Medical History .......................................................................................28
8.2.3.2
Study Specific Disease History................................................................29
8.2.4
Previous and Concomitant Medication....................................................29
8.3
Study Drug Accountability and Treatment Exposure..............................31
8.3.1
Study Drug Accountability ......................................................................31
8.3.2
Duration of Study Drug and PEG-J Exposure .........................................31
8.3.3
Prescribed Dose .......................................................................................32
8.3.4
Dose Administered...................................................................................32
8.4
Efficacy Analysis Variables.....................................................................33
8.4.1
Parkinson's Disease Diary (PD Diary).....................................................33
8.4.2
Unified Parkinson's Disease Rating Scale (UPDRS)...............................35
8.4.3
Clinical Global Impression – Improvement (CGI-I) ...............................37
8.4.4
Parkinson's Disease Questionnaire (PDQ-39) .........................................37
8.5
Safety Analysis Variables........................................................................38
8.5.1
Adverse Events ........................................................................................38
8.5.2
Safety Laboratory Data ............................................................................43
8.5.3
Vital Signs and Weight ............................................................................45
8.5.4
Electrocardiogram (ECG) Data................................................................47
8.5.5
Other Safety Analyses..............................................................................47
8.5.5.1
Complications with Infusion Device .......................................................47
8.5.5.2
PEG Tube and J Tube Replacements and Average Duration ..................49
8.5.5.3
Sleep Attacks ...........................................................................................50
8.5.5.4
Minnesota Impulsive Disorders Interview (MIDI) ..................................51
 


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8.5.5.5
Columbia Suicide Severity Rating Scale (C-SSRS) ................................52
8.5.5.6
Melanoma Check .....................................................................................52
8.5.5.7
Neurological Examination .......................................................................52
9.0
Statistical Analysis.................................................................53
9.1
Subject Disposition ..................................................................................53
9.2
Major Protocol Deviations.......................................................................55
9.3
Inclusion/Exclusion Criteria ....................................................................56
9.4
Demographic Data and Other Baseline Characteristics...........................57
9.4.1
Demographic Data ...................................................................................57
9.4.2
Other Baseline Characteristics.................................................................58
9.5
Medical and Neurological History...........................................................60
9.6
Concomitant Medication..........................................................................61
9.7
Drug Accountability.................................................................................63
9.8
Treatment Exposure.................................................................................64
9.9
Efficacy Analyses ....................................................................................65
9.10
Pharmacokinetic and Pharmacodynamic Analyses..................................67
9.11
Analysis of Safety....................................................................................67
9.11.1
Adverse Events ........................................................................................67
9.11.2
Clinical Laboratory Evaluation................................................................71
9.11.3
Vital Signs................................................................................................72
9.11.4
Electrocardiogram (ECG) Evaluations ....................................................73
9.11.5
Other Safety Analyses..............................................................................74
10.0
Changes to Planned Analyses...............................................76
10.1
Changes to the Analysis as Laid Down in the Protocol and
Amendments ............................................................................................76
11.0
References...............................................................................77
12.0
Appendices .............................................................................78
12.1
Schedules of Assessments........................................................................78
12.1.1
Schedule of Assessments – Amendment 1 ..............................................78
12.1.2
Schedule of Assessments – Amendment 2 ..............................................79
12.1.3
Schedule of Assessments – Amendment 3 ..............................................80
12.1.4
Schedule of Assessments – Amendment 4 ..............................................82
12.2
List of Tables ...........................................................................................84
 


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12.3
List of Listings .........................................................................................95
12.4
List of MedDRA Preferred Terms for Adverse Events of Special 
Interest......................................................................................................97
List of Tables
Table 1.
Visit Names and Labels ...........................................................................15
Table 2.
Visit Windowing Conventions.................................................................20
Table 3.
3005 Treatment Year ...............................................................................21
Table 4.
Criteria for Identification of Potentially Clinically Significant 
(PCS) Laboratory Values.........................................................................44
Table 5.
Criteria for Identification of Potentially Clinically Significant 
(PCS) Vital Sign and Weight Values.......................................................46
List of Figures
Figure 1.
LCIG United States Registration Program Overview..............................10
 


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3.0
Abbreviations and Definitions of Terms
General Abbreviations
AE
adverse event
ATC
Anatomical Therapeutic Chemical (class)
BMI
body mass index
bpm
beats per minute
CGI-I
Clinical Global Impression – Improvement
CLES
Carbidopa/levodopa enteral suspension 
CRF
case report form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DBP
diastolic blood pressure
DDT
data definition table
DSMB
data safety monitoring board
ECG
electrocardiogram
HLGT
High Level Group Term
HLT
High Level Term
kg
kilogram
LCIG
Levodopa-Carbidopa Intestinal Gel
LLT
Lowest Level Term
m
meter
max
maximum
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MIDI
Minnesota Impulsive Disorders Interview
min
minimum
mL
milliliter
mmHg
millimeters of mercury
N,n
number of observations
NA
not applicable
P(-Value)
exceedance probability for testing the null hypothesis
PCS
Potentially clinically significant
PD
Parkinson's Disease
 


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PDQ-39
Parkinson's Disease Questionnaire
PEG-J
Percutaneous endoscopic gastrostomy – with jejunal extension tube
PT
Preferred Term
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
S.I.
System International
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TLF/T,L,F
tables, listings and figures
UKPDS
United Kingdom Parkinson Disease Society
UPDRS
Unified Parkinson's Disease Rating Scale
WHO-DD
World Health Organization – Drug Dictionary 
Defined Terms
Day 1
First day of 3005 LCIG infusion
LDA
Duration of 3005 LCIG infusion
RFENDTN
Date of the last 3005 LCIG infusion
RFENDT2N
Date of the last 3005 PEG-J exposure
RFSTDTN
Date of the first 3005 LCIG infusion
 


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Clinical Domain Abbreviations
AE
Adverse events 
CM
Concomitant medication
DA
Drug accountability
DC
Device complications
DI
Device information
DM
Demographics
DS
Disposition
DV
Protocol deviations
EG
ECG test results
EX
Study drug exposure
HU
Healthcare utilization
IE
Inclusion/exclusion
KV
Key variables
LB
Laboratory test results
MH
Medical history
PE
Physical examination 
QS
Questionnaire
SC
Subject characteristics
VS
Vital signs
 


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4.0
Introduction
This statistical analysis plan (SAP), describes the analysis to be completed for 
Levodopa-Carbidopa Intestinal Gel (LCIG, also known as Carbidopa/Levodopa Enteral 
Suspension [CLES] in the United States) Study S187.3.005 (Study 3005), dated 
17 December 2013, which incorporates Global Amendments 1, 2, 3 and 4 and UK 
Amendments 2 and 3.01.  It contains a technical elaboration of the principal features of 
the statistical analyses described in the protocol and is intended to guide the statistical 
programming work for the interim analysis to be conducted following the interim 
database lock completed in October 2015 as well as for the final analysis to be 
summarized in the Clinical Study Report (CSR).
A previous interim analysis was completed as described in SAP Version 2.  For the 
previous interim analysis, all subject assessments completed on or before 04 May 2012 
were included.
For the October 2015 interim analysis, all subject assessments completed on or before 
30 September 2015 (the "Cutoff Date") will be included in the analysis. 
All analysis data sets and statistical output will be produced by the Biostatistics 
department of Quintiles, Inc, Research Triangles Park, North Carolina, USA using the 
SAS® system Version 9.4 or higher.1
5.0
Summary of the Protocol and Amendments
5.1
Study Schedule of Assessments
The assessments performed in Study 3005 under Amendments 1, 2, 3 and 4 are 
summarized in the Study Schedules of Assessments (Appendix 12.1.1, Appendix 12.1.2, 
Appendix 12.1.3, and Appendix 12.1.4).  Subject visit days should ideally match the 
target clinic visit days; however, a 14-day visit window will be allowed as necessary.
 


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5.2
Overall Study Plan
This is a Phase 3B, open-label, multicenter study of the long-term safety and tolerability 
of LCIG in the treatment of approximately 275 advanced PD subjects with a good 
therapeutic response on LCIG with regard to the treatment of persistent severe motor 
fluctuations.  The study will be conducted at approximately 70 centers.
Study 3005 is an extension study in the LCIG United States registration program.  In this 
program, subjects who completed 12 weeks of treatment in double-blind double-dummy 
Study S187.3.001 (3001) or Study S187.3.002 (3002) were eligible to enroll in the 
12-month open-label Study S187.3.003 (3003) and then in Study 3005.  All subjects in 
Study 3001 and Study 3002 received a PEG-J and were randomized to receive either 
LCIG and placebo capsules or levodopa-carbidopa capsules and placebo gel.  All subjects 
in Study 3003 received LCIG.  Subjects who completed the 12-month open-label 
Study S187.3.004 (3004), were also qualified to enroll in Study 3005.  Subjects in Canada 
were allowed to participate with a minimum of 6 months of exposure to LCIG in 
Study 3004.
Figure 1.
LCIG United States Registration Program Overview
Following informed consent, subjects had their inclusion/exclusion criteria assessed prior 
to beginning treatment in Study 3005.  Subjects are allowed to have a caregiver, if 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 


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appropriate, to assist them with study requirements, i.e., care of the pump and tubing, etc. 
and the caregiver will have been trained accordingly.
The initial LCIG dose in Study 3005 was identical to the dose that the subject was 
receiving at the end of the previous open-label LCIG study.  Subsequent dose adjustments 
will be made as clinically indicated by the Investigator.  In addition to the morning dose 
and the continuous infusion, subjects will be allowed to self-administer additional doses 
of LCIG to address immediate subjective needs, such as the deterioration of motor 
function.  If a subject finds it necessary to self-administer an increasing number of extra 
doses (> 5/day) of LCIG, they will be instructed to contact the Investigator for appropriate 
follow-up care (adjustment of continuous infusion) as needed.
In this open-label study, a recommendation will be made to Investigators to withhold 
concomitant PD treatments if deemed medically safe and clinically appropriate.  The 
initiation of additional PD medication may be medically indicated and is allowed at the 
discretion of the Investigator.  Also, the dosages of these other PD medications can be 
adjusted upward or downward as needed based on the status of the subject's condition or 
the development of adverse effects; resumption of discontinued PD medications may also 
be necessary.
The final visit in the previous open-label LCIG study will provide baseline assessments 
for Study 3005.  Subjects will be reassessed every 6 months for the appropriateness of the 
continuation of treatment with LCIG.  If the subject is deemed inappropriate for continued 
treatment by the Investigator, the subject will be discontinued from treatment.  Subjects 
who discontinue LCIG treatment will have the PEG-J removed, and a follow-up clinic 
visit will occur 1 week later.
Safety assessments include physical examination, neurological exam, orthostatic vital 
signs, weight, adverse event monitoring, assessment of impulsive behavior and sleep 
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At each visit, adverse events or complications with the infusion device (i.e., the tubing 
system and the pump) will also be recorded and reported.  Tube placement will be 
checked by radiography if there is a clinical indication that the tube has been displaced.  
The tube will be repositioned, if needed, to the original placement site just beyond the 
ligament of Treitz.  At each visit the tube insertion site, including the stoma, will also be 
inspected.  On a yearly basis, at a minimum, an assessment will be made of the need for a 
replacement of the PEG-J.  The frequency of replacement should be in accordance with 
local practice.
Protocol Amendment 4 added the following efficacy assessments at US sites only:  
Parkinson's Disease Diary, the Unified Parkinson's Disease Rating Scale (UPDRS), and 
the Parkinson's Disease Questionnaire-39 (PDQ-39).
The protocol duration is planned until the finished product is available commercially in 
the respective countries where subjects are participating in the study.
5.3
Treatments
LCIG is a homogeneous suspension of levodopa (20 mg/mL) and carbidopa (5 mg/mL) in 
an aqueous intestinal gel (carboxymethycellulose).  LCIG is delivered to the proximal 
small intestine through a jejeunal extension tube inserted via percutaneous endoscopic 
gastrostomy (PEG-J).  The intestinal gel is dispensed in a medication cassette reservoir of 
100 mL, designed to be connected to a portable subject-operated pump.  LCIG is to be 
administered over approximately 16 waking hours.  At night, after disconnecting the 
pump for sleeping, the tubing is to be flushed with potable water.
Each subject's LCIG dose will be individually optimized.  The initial LCIG dose will be 
identical to the dose that the subject was receiving at the end of the previous open-label 
LCIG study.  Dose adjustments, either upward or downward, can be made at any time 
throughout the study based on the clinician's judgment of effectiveness.  No dosing 
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The total daily dose of LCIG infusion will be composed of three components:  the 
morning dose, the continuous maintenance infusion dose, and extra doses.  The morning 
dose is administered as a bolus infusion by the pump to fill the dead space of the intestinal 
tube and rapidly achieve therapeutic dose level (within 10 to 30 minutes).  The total 
morning dose is typically 5 – 10 mL (100 – 200 mg levodopa) and will usually not exceed 
15 mL (300 mg levodopa).  The continuous maintenance dose is administered over 
approximately 16 waking hours.  The infusion rate for the continuous maintenance dose is 
typically 2 – 6 mL/hour (40 – 120 mg levodopa/hour) and will usually be within 
0.5 – 10 mL/hour (10 – 200 mg levodopa/hour).  During the continuous infusion, subjects 
may self-administer a pre-set extra infusion dose (at intervals of no less than 2 hours) to 
address immediate medical needs, such as the rapid deterioration of motor function.  The 
extra infusion dose will normally be set at 0.5 – 2.0 mL (10 – 40 mg levodopa). In rare 
cases a higher dose may be needed.
5.4
Data Safety Monitoring Board
Prior to the completion of the pivotal, Phase 3 studies, Study 3001 and Study 3002, a Data 
Safety Monitoring Board (DSMB) reviewed the safety data in accordance with the DSMB 
Charter.  Planned safety analyses for the DSMB were presented in a separate document 
and are not discussed in any detail in the body of this SAP.
6.0
General Definitions, Methods, Naming Conventions 
and Data Handling
In order to avoid ambiguity during the analysis, a number of definitions and conventions 
for data handling are described in this section.
The following information for each subject will be summarized in a Key Variable (KV) 
derived dataset:
●
Treatment group as described in Section 6.2.
●
Reference dates as described in Section 6.4.1.
●
Inclusion in subject samples as described in Section 8.1.1.
 


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6.1
General Methodology and Presentation
The default summary statistics for quantitative variables will be the number of 
observations (n), mean, standard deviation (SD), median, minimum (min) and maximum 
(max), for those subjects with data.
All summary statistics will be rounded (using the SAS® function ROUND) and presented 
to one more decimal place than the raw value, except for the minimum and maximum 
values that will be presented with the same decimal precision as the raw value.
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing 
data per category will be the default summary presentation, and where appropriate and 
present, the number of missing values as a "Missing" category.
Percentage values are to be rounded and presented to one decimal place, for example, 
52.3%.  If the calculated percentage is > 0.0% but < 0.1% then < 0.1% is to be presented 
in the relevant table and/or listing.
The exceedance probabilities for testing the null hypothesis will be denoted by "P value."  
P values are to be rounded (using the SAS® function ROUND) and printed with 
three decimals.  P values below 0.0005 will be denoted as < 0.001.
6.2
Treatment Group Names and Labels
Statistical output (SAS® tables) will be presented.  The treatment name/label to be used in 
the tables, listings and figures (TLFs) is defined in the table below.
Treatment Code Number
Treatment Description
Treatment Label
1
Levodopa-carbidopa intestinal gel (LCIG) 
supplied as a water suspension of 20 mg/mL 
levodopa and 5 mg/mL carbidopa 
Levodopa-Carbidopa 
Intestinal Gel
 


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6.3
Visit Names and Labels
The visit names/labels to be used in the analysis data sets and in the TLFs are defined in 
Table 1 below.
Table 1.
Visit Names and Labels
Visit Number
Visit Name
Visit Label
1
Baseline
Baseline
2
Month 6
Month 6
3
Month 12
Month 12
4
Month 18
Month 18
5
Month 24
Month 24
6
Month 30
Month 30
7
Month 36
Month 36
8
Month 42
Month 42
9
Month 48
Month 48
10
Month 54
Month 54
11
Month 60
Month 60
12
Month 66
Month 66
13
Month 72
Month 72
14
Month 78
Month 78
15
Month 84
Month 84
99
Follow-up
Follow-up
6.4
Day Numbers, Study Periods and Visit Windows:  Related 
Definitions
6.4.1
General Definitions
Assessment days will be related to the date of the first infusion of 3005 study drug 
(First 3005 LCIG Infusion).  Baseline is defined in Section 6.4.5 (Baseline Period).  The 
Cutoff Date for the 2015 interim analysis will be 30 September 2015.  Assessments and/or 
measurements performed after the Cutoff Date, adverse events or device complications 
with start dates after the Cutoff Date, and concomitant medications with start dates after 
 


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the Cutoff Date will not be included in the 2015 interim analysis.  No cutoff date will be 
applied to the analysis for the final CSR.
The following reference dates will be defined for all subjects in the All Subjects 
Consented subject sample defined in Section 8.1.1.
●
Date of the First 3005 LCIG Infusion (Day 1, RFSTDTN):
The actual dates of study drug administration are not recorded in the 3005 
database.  The dates when 3005 study drug is dispensed are recorded in the DA 
raw data panel.  For analysis, the date of the first 3005 LCIG infusion will be 
defined as the first date that 3005 study drug was dispensed to the subject.  The 
visit date recorded in the DM raw data panel will be used if the date the 
first study drug was dispensed is not available.
The date of the first 3005 LCIG infusion will be defined as Day 1 and is the 
key variable RFSTDTN and is used in the calculation of relative days.
●
Date of the Last 3005 LCIG Infusion (RFENDTN):
For subjects who have prematurely discontinued or completed the study, the 
date of the last 3005 LCIG infusion will be the earliest of 1) the date of last 
study drug administration collected on the DS raw data panel, 2) the date of 
discontinuation or study completion collected on the DS raw data panel and 
3) the Cutoff Date (interim analysis only).
For the 2015 interim analysis, the date of the last 3005 LCIG infusion for all 
ongoing subjects will be the Cutoff Date.
●
Duration of 3005 LCIG Infusion (LDA):
The Duration of 3005 LCIG Infusion or exposure to treatment is equal to the 
day number of the Last 3005 LCIG Infusion (LDA) and is derived as follows 
from the previous two dates:
LDA (days) = (Date of the Last 3005 LCIG Infusion [RFENDTN] – Date of 
the First 3005 LCIG Infusion [RFSTDTN]) + 1
LDA then indicates the relative day of the last 3005 LCIG infusion for each 
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●
Date of Last 3005 PEG-J Exposure (RFENDT2N):
LCIG is administered as part of a therapeutic system that includes devices and 
implantation procedures.  Subjects who discontinue LCIG therapy are to have 
their PEG-J removed.
For subjects who have prematurely discontinued or completed the study, and 
have reported a final PEG-J removal on the DI raw data panel that is after their 
last day of study drug administration and before the Cutoff Date (interim 
analysis only), their date of last 3005 PEG-J exposure will be the date of 
PEG-J removal.  For all other subjects who have prematurely discontinued or 
completed the study, their date of last 3005 PEG-J exposure will be the earlier 
of 1) the date of discontinuation or study completion collected on the DS raw 
data panel, and 2) the Cutoff Date (interim analysis only).
For the 2015 interim analysis, the date of the last 3005 PEG-J exposure for all 
ongoing subjects will be the Cutoff Date.
The date of the last 3005 PEG-J exposure is the key variable RFENDT2N.
6.4.2
Initial Screening Period
Height and background information related to medical and neurological history and 
PD diagnosis was only collected during the Screening Period of the first LCIG study that 
a subject participated in.  For example, subjects who entered the 3005 study after 
completing the 3003 open-label study would have completed one of the two Phase 3, 
double-blind studies, Study 3001 or 3002, before their enrollment in Study 3003.  For 
these subjects, certain background information, e.g., medical history, neurological history 
and PD diagnosis information, was only collected prior to Study 3001 or 3002.  This 
information will be retrieved from the relevant study databases and summarized for the 
subjects enrolled in Study 3005.
6.4.3
Initial PEG-J Placement
Subjects enrolled in Study 3005 had their initial PEG-J placement in Study 3001, 3002 or 
3004.  To allow the overall duration of PEG-J exposure to be summarized for each subject 
 


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in Study 3005, the date of initial PEG-J placement will be retrieved from the relevant 
study database.
6.4.4
Initial LCIG Infusion
Subjects enrolled in Study 3005 had their first LCIG infusion in the same study as their 
initial PEG-J placement (Studies 3001, 3002 or 3004) except for subjects who received 
levodopa-carbidopa capsules and placebo gel in Study 3001 or Study 3002.  These 
subjects had their first LCIG infusion in Study 3003.  To allow the overall duration of 
LCIG exposure to be summarized for each subject in Study 3005, the date of initial LCIG 
infusion will be retrieved from the relevant study database.
For US subjects who completed Daily Dosing Diaries in Study 3005 following 
Amendment 4, the total daily levodopa dose at the end of the subject's initial LCIG 
titration period will be retrieved from the relevant database to allow the change in dose 
from initial titration to final Study 3005 visit to be determined.
To provide context for changes in efficacy measures observed during Study 3005, the 
respective change observed between initial LCIG infusion and Study 3005 final visit will 
be determined and summarized.  For subjects who completed efficacy assessments in 
Study 3005, their baseline value from the study in which they had their first LCIG 
infusion will be retrieved from the relevant database and considered their value at initial 
LCIG infusion.
6.4.5
Baseline Period for Study 3005
The Baseline Period for Study 3005 is defined as the time before the first 3005 LCIG 
infusion.  For efficacy measures, the final value in the previous study (Study 3003 or 
Study 3004) will be retrieved from the relevant database and will be considered the 3005 
baseline value.  For safety evaluations, the final assessment in the previous open-label 
LCIG study or in 3005 that is on or before the date of the first 3005 LCIG infusion will be 
used as the 3005 Baseline value.  For systolic blood pressure, diastolic blood pressure and 
 


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pulse, the final assessment where results are present for both the supine and standing 
position will be considered baseline.
6.4.6
Treatment Period
Data collected on the Date of the First 3005 LCIG Infusion (Day 1) will be assigned to the 
Baseline Period.  However, adverse events and concomitant medications starting on Day 1 
will be assigned to the Treatment Period (worst case scenario).
A Gap Period (number of days) is defined to include data collected after the end of the 
relevant Treatment Period in the analysis.  For this study, the Gap Period will be 30 days 
for adverse events and 1 day for all other assessments.
For efficacy assessments the Treatment Period is defined as the Period from the Date of 
the First 3005 LCIG Infusion up to and including the Date of the Last 3005 LCIG 
Infusion + Gap Period (1 day).  For safety assessments the Treatment Period is defined as 
the Period from the Date of the First 3005 LCIG Infusion up to and including the Date of 
the Last 3005 PEG-J Exposure + Gap Period (30 days for adverse events and 1 day for all 
other assessments).
The Endpoint value for a variable is defined as the last non-missing value assigned to the 
Treatment Period for the subject.
6.4.7
Post-Treatment Period
For efficacy assessments, the Post-Treatment Period is defined as the period after the Date 
of the Last 3005 LCIG Infusion + Gap Period (1 day).  For safety assessments, the 
Post-Treatment Period is defined as the period after the Date of the Last 3005 PEG-J 
Exposure + Gap Period (30 days for adverse events and 1 day for all other assessments).
 


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6.4.8
Visit Windowing Conventions
Assessments will be assigned to the Baseline Period if the date is on or before the Date of 
the First 3005 LCIG Infusion as defined in Section 6.4.1 and to the Post-Treatment Period 
if the date is after the end of the relevant Treatment Period as defined in Section 6.4.6.
Assignment of assessments to visits during the Treatment Period will use visit windows 
based on the day of the assessment relative to the Date of the First 3005 LCIG Infusion as 
described in Table 2 below.
Table 2.
Visit Windowing Conventions
Visit Label
Target Visit Day
Study Day Range
Baseline
≤ 1
Month 6
180
2 to 270
Month 12
360
271 to 450
Month 18
540
451 to 630
Month 24
720
631 to 810
Month 30
900
811 to 990
Month 36
1080
991 to 1170
Month 42
1260
1171 to 1350
Month 48
1440
1351 to 1530
Month 54
1620
1531 to 1710
Month 60
1800
1711 to 1890
Month 66
1980
1891 to 2070
Month 72
2160
2071 to 2250
Month 78
2340
2251 to 2430
Month 84
2520
> 2430
If a subject has two or more assessments in the same visit window, the assessment closest 
to the target visit day will be used.  If two assessments are equidistant from the target visit 
day, the later assessment will be used.
Each reported post-baseline lab and vital sign measurement shall be evaluated to 
determine if it meets potentially clinically significant criteria.  For all other analyses of 
 


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labs and vital signs, if two measurements are on the same date, the average will be 
calculated and treated as the value for that date.
6.4.9
3005 Treatment Year
The following events will be summarized by 3005 Treatment Year using the study day 
intervals described in Table 3 below: premature study discontinuations, prevalence of 
concomitant anti-parkinsonian medication use, the incidence and prevalence of adverse 
events, the incidence of device complications, and the number of PEG tube and J-tube 
replacements.
Table 3.
3005 Treatment Year
3005 Treatment Year
Study Day Range
Year 1
2 to 365
Year 2
366 to 730
Year 3
731 to 1095
Year 4
1096 to 1460
Year 5
1461 to 1825
> Year 5
> 1825
6.5
Handling of Missing Data
The handling of missing data, if applicable, is discussed in Section 8.0 (Analysis 
Variables:  Definitions, Derivations, Calculations and Conventions).  Presentation of 
missing data is discussed in the relevant subsections of Section 9.0 (Statistical Analysis).
7.0
Objectives
7.1
Primary Objective
The primary objective of this study is to provide, under well controlled conditions, 
continued access to LCIG treatment to subjects who have already participated in an open 
label efficacy and safety trial with the same treatment (Study S187.3.003 or 
 


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Study S187.3.004), and in whom the need for such continuation is indicated, as confirmed 
by periodic evaluation, until the product is commercially available.
7.2
Secondary Objectives
To assess the long-term safety and tolerability of the LCIG therapeutic system by the 
following:
●
Physical examination, including weight
●
Neurological examination
●
Vital signs
●
Resting ECGs
●
Clinical laboratory assessments including biochemistry, hematology, 
urinalysis, and special labs to monitor for vitamin deficiencies
●
Concomitant medication usage
●
Adverse event monitoring, including for the development of sleep attacks, 
melanoma, or excessive impulsive behavior
●
Monitoring complications of the infusion device
●
Tolerability assessed by number of subjects who complete the study
To assess the maintenance of efficacy using the following data collected from US 
subjects:
●
Off time, On time with troublesome dyskinesia, and On time without 
troublesome dyskinesia as measured by the Parkinson's Disease Diary
●
UPDRS total score, Parts I, II, III and IV scores, and dyskinesia item score
●
PDQ-39 summary index and domain scores
 


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8.0
Analysis Variables:  Definitions, Derivations, 
Calculations and Conventions
8.1
Subject Disposition
8.1.1
Subject Samples
There will be three hierarchical subject samples of interest.
The "All Subjects Consented" subject sample will be used to summarize subject 
disposition and will consist of all subjects who:
●
Gave their informed consent.
The Safety subject sample will consist of all subjects who:
●
Were in the "All Subjects Consented" subject sample and
●
Received at least 1 infusion of 3005 study drug
The Safety subject sample will be used for all analyses of safety unless noted otherwise.
The Efficacy subject sample will consist of all subjects who:
●
Were in the Safety subject sample and
●
Have at least 1 efficacy assessment in 3005
The Efficacy subject sample will be used for all analyses of efficacy unless noted 
otherwise.
For subjects enrolled in the United States, efficacy assessments were added with Protocol 
Amendment 4.  To evaluate efficacy and safety in these subjects, analyses will be 
completed including only the subjects in the relevant subject sample who were enrolled in 
the United States (the "US Subset").
 


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To evaluate the association between polyneuropathy events and vitamin deficiencies, 
additional analyses will be completed for the subset of subjects who experienced a TEAE 
coded to either the Standardized MedDRA Query (SMQ) of Peripheral Neuropathy –
narrow search or Guillain-Barre Syndrome – narrow search (the "Narrow Polyneuropathy 
Subset").
8.1.2
Subgroups
Subgroups to evaluate the robustness of efficacy observations will be based on the 
following:
●
the study in which the subject received their first LCIG infusion (3001/2, 3003, 
3004)
●
troublesome dyskinesia at initial LCIG infusion (< 1 hour, > 1 hour as 
recorded on the PD Diary) 
●
total daily levodopa dose at initial LCIG infusion (< 1250 mg/day, 
> 1250 mg/day ), and
●
levodopa monotherapy in Study S187.3.005 (yes, no)
To evaluate the robustness of observations, the change in total daily levodopa dose will be 
evaluated after grouping subjects by the study in which they received their first LCIG 
infusion.
Subgroups defined for exploratory analyses of safety will include gender, age category 
(< 65, ≥ 65 years), duration of Parkinson's disease (< 10 years, ≥ 10 years) and country.
Due to the similarity in study design, Studies 3001 and 3002 will be combined and 
considered a single study (Study 3001/3002) for the subgroup analysis based on the study 
in which the subject received their first LCIG infusion.
8.1.3
Protocol Deviations
The number and percentage of subjects with one or more of the following major protocol 
deviations will be summarized overall as well as by category:
 


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●
Those who entered the study even though they did not satisfy the entry criteria.  
adherence to the inclusion and exclusion criteria will be the determining factor 
for this category of protocol deviations.
●
Those who developed withdrawal criteria during the study but were not 
withdrawn.  The only criterion defined in the protocol that required withdrawal 
from the study was the development of melanoma.
8.1.4
Inclusion/Exclusion Criteria
The study specific inclusion/exclusion criteria are presented in Section 8.1 and Section 8.2 
of the protocol.
8.1.5
Subject Enrollment and Disposition
As previously described, Study 3005 is an extension study.  Subjects will be assigned to 
an enrollment cohort based on the study in which they received their first LCIG infusion.  
Due to the similarity in study design, Study 3001 and Study 3002 will be considered a 
single enrollment cohort.  The number and percentage of subjects in each of the following 
enrollment cohorts will be summarized:
●
Subjects who received their first LCIG infusion in Study S187.3.001 or 
Study S187.3.002
●
Subjects who received their first LCIG infusion in Study S187.3.003
●
Subjects who received their first LCIG infusion in Study S187.3.004
Subjects are expected to continue in the study until commercial LCIG becomes available 
to them.  If commercial LCIG becomes available to a subject, a final visit shall be 
scheduled and the subject will be regarded as having completed the study if they complete 
this final visit.  If at any time after providing informed consent, a subject prematurely 
discontinues their participation in the study, the primary reason for premature 
discontinuation shall be recorded on the "Study Termination" CRF.  The primary reason 
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●
Adverse Event
●
Lack of Efficacy
●
Lost to Follow-up
●
Withdrew Consent
●
Administrative
●
Protocol Violation
Premature discontinuations will be summarized by 3005 treatment year after allocating 
each premature discontinuation to a 3005 treatment year based on the study day of the 
subject's last dose date and the study day intervals described in Section 6.4.9.
8.2
Subject Characteristics
8.2.1
Demographic Data
Standard demographic data collected includes:
●
Date of Birth
●
Gender
●
Race (American Indian or Alaska native, Asian, black of African heritage or 
African American, native Hawaiian or other Pacific Islander, or white)
●
Ethnicity (Hispanic or Latino)
●
Country
Age (years) will be derived in SAS® using Date of Birth, and calculated relative to Day 1, 
as follows:
Age (years) = Day1_Y – Birth_Y – (0 < Day1_M < Birth_M OR
[Day1_M = Birth_M AND 0 < Day1_D < Birth_D])
Where:
Day1_D:  Day of Day 1 date.
Day1_M:  Month of Day 1 date.
Day1_Y:  Year of Day 1 date.
 


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Birth_D:  Day of Birth.
Birth_M:  Month of Birth.
Birth_Y:  Year of Birth.
Where the Date of Birth is incomplete the following convention will be used:
●
Where the day is missing and month and year are available the day will be 
completed as the 15th.  For example, Date of Birth specified as – JAN1980 will 
be completed as 15JAN1980.
●
If the day and month are missing and the year is available the day and month 
will be completed as 02JUL (the 183rd day of the year).  For example, Date of 
Birth specified as – 1980 will be completed as 02JUL1980.
8.2.2
Other Baseline Characteristics
Other Baseline characteristics include:
Vital Signs:
●
Height (m) as measured during the Initial Screening Period
●
Weight (kg)
●
BMI (kg/m2)
●
Body Temperature (degrees Celsius) including route of measurement
●
Systolic Blood Pressure (SBP [mmHg]) supine, standing and orthostatic
●
Diastolic Blood Pressure (DBP [mmHg]) supine, standing and orthostatic
●
Pulse Rate (beats per minute [bpm]) supine, standing and orthostatic
Study specific calculations and/or conversions include:
Height (m):  If applicable, height will be converted from inches to meters for the 
calculation of Body Mass Index (BMI), using the following formula:
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Weight (kg):  If applicable, weight will be converted from pounds to kilograms for the 
calculation of BMI, using the following formula:
Weight (kg) = (XX pounds * 0.4536) and presented to one decimal precision.
Body Mass Index calculated as:
BMI (kg/m2) = Weight (kg)/Height (m)2 and presented to one decimal precision.
Temperature (degrees Celsius):  If applicable, temperature will be converted from 
degrees Fahrenheit to Celsius, using the following formula:
Temperature (degrees C) = (XX degrees F – 32)/1.8 and presented to one decimal 
precision.
8.2.3
Medical History and Other Disease History
8.2.3.1
Medical History
Medical history (MH) is defined as any condition, with the exception of the study 
indication, that the subject reported during the Initial Screening Period.  Medical history 
will include findings reported on either the medical history or neurological history CRF.
Medical history findings will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA),2 Version 14.0 or later and will be presented by primary System 
Organ Class (SOC) and by Preferred Term (PT) within SOC.  The SOCs and PTs will be 
sorted alphabetically at each coded level.  Medical history will be reported on a by-subject 
basis.  This implies that if the subject reported the same condition (conditions mapped to 
the same PT) repeatedly, the condition will only be counted once.  The earliest date will 
be regarded as the start date of the condition and the last available date, as the stop date of 
the condition.
Missing or partial dates for medical history will not be completed, for example, if only a 
month and year are available as – FEB2005, the day will not be imputed in order to 
 


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complete the date.  If "End Date" information is not available it will be assumed that the 
finding is "Ongoing" at the time of enrollment in the study.
8.2.3.2
Study Specific Disease History
Study specific disease history collected during the Initial Screening Period included the 
month and year of initial PD diagnosis and assessment of the following modified United 
Kingdom Parkinson Disease Society (UKPDS) brain bank criteria for Parkinsonian 
Syndrome:
●
Diagnosis of bradykinesia (slowness of initiation of voluntary movement with 
progressive reduction in speed and amplitude of repetitive actions)
●
Diagnosis of muscular rigidity
●
Diagnosis of 4 – 6 Hz resting tremor
●
Diagnosis of postural instability not caused by primary visual, vestibular, 
cerebellar or proprioceptive dysfunction
The duration of PD will be calculated as the time (in years) from the initial diagnosis of 
PD until the subject entered the Initial Screening Period.  Missing months for initial PD 
diagnosis will be set to January resulting in the earliest possible onset and the longest 
possible duration.
8.2.4
Previous and Concomitant Medication
Medications are classified according to active drug substance using the World Health 
Organization-Drug Dictionary (WHO-DD), 01 March 2011.3  The WHO drug code has 
11 digits.  The generic name (required for presentation in the tables and listings) is 
defined by the first 6 of the 11 digits.  In addition, Anatomical Therapeutic Chemical 
(ATC) classes are assigned to the drug code.  In this study, ATC codes are defined to the 
third level.  Although there can be multiple ATC classes for a drug, each drug will be 
linked with one ATC class which will be assigned manually during the coding process, 
based on information about the indication and route in relation to the study therapeutic 
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Previous or prior medications are defined as medications that were being used at the end 
of the previous study and were continuing to be used when the subject entered the 
3005 study.  Summaries of previous medications will focus on anti-parkinsonian 
medications.
Concomitant medications (CM) are defined as medications taken at any time during the 
Treatment Period defined for safety assessments in Section 6.4.6 and include medications 
started prior to the first 3005 LCIG infusion but continued during the study as well as 
medications started at or after the first 3005 LCIG infusion and before the last 3005 
PEG-J exposure.
Missing and/or incomplete dates for medications are imputed in a manner resulting in the 
earliest onset or the longest duration.  However, the Stop Date will not be imputed if the 
medication is reported as "Ongoing."
Technically, this will be done as follows:
●
If the day is missing and the month and year are available, the start (stop) date 
will be completed as the first (last) day of the month.
●
If the day and month are missing and the year is available, the start (stop) date 
will be completed as the first (last) day of the year.
●
If the date is completely missing, the start (stop) date will be completed as a 
very early (late) date, for example, 01JAN1000 (01JAN3000).
The prevalence of concomitant anti-parkinsonian medication (CM) use during each 
3005 Treatment Year will be summarized using the study day intervals described in 
Section 6.4.9.  CM start and stop days will be calculated relative to the start of 
3005 LCIG infusion (RFSTDTN) as follows:
CM Start Day = (CM Start Date – Start of 3005 LCIG Infusion + 1)
CM Stop Day = (CM Stop Date – Start of 3005 LCIG Infusion + 1)
 


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A subject will be considered to have taken a specific CM during an interval if:
●
the CM Start Day is within the study day range for the interval and was not 
greater than the day of the last 3005 LCIG infusion, or 
●
the CM Start Day is less than the lower limit of the study day range and the 
CM Stop Day is later than the lower limit of the study day range or missing.
Note that this definition assumes that a missing CM Stop Day is an indication that the use 
of the CM is ongoing.  The denominator for percentage calculations for each interval will 
be the number of subjects whose last day of 3005 LCIG infusion was within or after the 
interval day range.
8.3
Study Drug Accountability and Treatment Exposure
8.3.1
Study Drug Accountability
LCIG is dispensed in 100 mL medication cassette reservoirs that are designed to be 
connected to a portable subject-operated pump.  Subjects are to return all used as well as 
all unused cassettes to the site at each clinic visit.
8.3.2
Duration of Study Drug and PEG-J Exposure
The duration of LCIG exposure as well as the duration of PEG-J exposure will be 
summarized for 3005 as well as overall.  The duration of 3005 LCIG infusion (LDA) is 
described in detail in Section 6.4.1 (General Definitions).  The duration of 3005 PEG-J 
exposure will be calculated as the Date of the Last 3005 PEG-J Exposure (as defined in 
Section 6.4.1) – the Date of the First 3005 LCIG Infusion (as defined in Section 6.4.1) +1.  
The total subject-years of exposure will be calculated as the sum of all subject exposures 
in days divided by 365.25.
As previously described, Study 3005 is an extension of the previous Studies 3001, 3002, 
3003, and 3004.  To determine the overall duration of each subject's LCIG and PEG-J 
exposure, the date of initial PEG-J placement and the date of initial LCIG infusion will be 
retrieved from the relevant study database.  The overall duration of LCIG infusion will be 
 


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calculated as the Date of the Last 3005 LCIG Infusion – the Date of the Initial LCIG 
Infusion +1.  The overall duration of PEG-J exposure will be calculated as the Date of 
Last 3005 PEG-J Exposure – the Date of the Initial PEG-J placement +1.
8.3.3
Prescribed Dose
The prescribed dose of LCIG is comprised of a morning dose, a continuous maintenance 
dose, and an extra dose to be administered as needed.  Each subject's pump settings for the 
morning dose, extra dose and continuous infusion rate are individually optimized and 
programmed by the Investigator at a clinic visit.  Subjects self-administer LCIG by 
starting and stopping the pump each day and by infusing extra doses as needed during the 
continuous infusion.
8.3.4
Dose Administered
Beginning with Protocol Amendment 4, subjects enrolled at US sites were to record all 
LCIG infusions (including pump start time, pump stop time and the time of any extra dose 
administration) and all oral levodopa/carbidopa doses on a Daily Dosing Diary for the 
3 days before each clinic visit.  The average total daily LCIG dose at the final 3005 visit 
will be calculated by summing the total mL of LCIG infused on each Daily Dosing Diary 
completed within 14 days of the final Daily Dosing Diary and dividing by the number of 
diaries recorded.  The average total daily dose of LCIG will then be converted to the 
average total daily dose of levodopa using the conversion factor of 1 mL LCIG = 20 mg 
levodopa.  Only diaries reporting at least 12.8 hours of pump operation will be included in 
this calculation.
The average total daily levodopa dose at the final 3005 visit will be summarized with 
descriptive statistics for each component (morning dose, continuous maintenance dose, 
and extra dose) as well as for the total levodopa dose.  Each subject's total daily levodopa 
dose at the end of their initial LCIG titration in Studies 3001, 3002, 3003 or 3004 will be 
retrieved from the relevant database.  The total daily levodopa dose at the end of initial 
LCIG titration and the change in total daily levodopa dose from the end of initial LCIG 
titration to final 3005 visit will be summarized with descriptive statistics.  To evaluate the 
 


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robustness of observations, the same summary will be prepared after grouping subjects 
based on the study in which they received their first LCIG infusion.
8.4
Efficacy Analysis Variables
The original Protocol included the following efficacy measures:
●
Parkinson's Disease Diary4
●
Parkinson's Disease Questionnaire (PDQ-39)
●
Clinical Global Impression – Improvement (CGI-I)
These measures were removed from the schedule of assessments with Protocol 
Amendment 1.  With Protocol Amendment 4, the following measures were added to the 
schedule of assessments for subjects enrolled at US sites:
●
Parkinson's Disease Diary
●
Unified Parkinson's Disease Rating Scale (UPDRS)
●
Parkinson's Disease Questionnaire (PDQ-39)
The change in each efficacy measure from 3005 baseline to 3005 final visit will be 
determined and summarized.  To provide context, the change in each efficacy measure 
from initial LCIG infusion to 3005 final visit will also be determined and summarized.
8.4.1
Parkinson's Disease Diary (PD Diary)
The core of the Parkinson's Disease Diary (PD Diary)4 is the questionnaire that the subject 
will use to record parkinsonian symptoms.  The subject and/or caregiver will be prompted 
to answer the PD questionnaire on whether the subject has been "on" without dyskinesia, 
"on" with non-troublesome dyskinesia, "on" with troublesome dyskinesia, "off," or 
"asleep."  The diary is completed for the full 24 hours of each day reflecting both time 
awake and time asleep.  On the recording days, subjects will be instructed to make an 
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asleep.  Beginning with Protocol Amendment 4, US subjects were to complete a PD Diary 
during the 3 consecutive days prior to each clinic visit.
Average normalized "off" time will be calculated as follows:
Valid Diary Days
1.
For subjects with more than one observation for the same 30 minute time period, 
the 30-minute time will be evenly split among the number of observations checked.
2.
Subjects who do not complete at least 12 awake hours of symptom diary data (not 
including "ASLEEP" time) will have that daily data set to missing (i.e., will not be 
considered as a valid symptom diary day).  There will be no imputation of data for 
these diary days.
Absolute and Normalized Daily "OFF" Time
3.
Absolute "off" time, "on" time without dyskinesia, "on" time with non-troublesome 
dyskinesia, "on" time with troublesome dyskinesia and "asleep" time will be 
determined from each 24-hour PD symptom diary.
4.
Daily awake time is the sum of absolute "off" time, "on" time without dyskinesia, 
"on" time with non-troublesome dyskinesia, and "on" time with troublesome 
dyskinesia.
5.
"Off" time, "on" time without dyskinesia, "on" time with non-troublesome 
dyskinesia, and "on" time with troublesome dyskinesia will be normalized to a 
16 hour waking time due to the variance in sleep patterns.  For example, 
normalized "off" time is calculated as:
Normalized "off" time = (Absolute "off" time/Awake time) * 16.
All times are expressed in decimal hours.
 


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Daily Average
6.
Valid symptom diary days (at least 12 awake hours) will be used to compute the 
average daily normalized "off" time.  For post-baseline visits, the valid symptom 
diary day must be within 7 days of the clinic visit but not on or after the day of the 
clinic visit.  If more than 3 valid symptom diary days are available, the 3 days 
closest to the clinic visit will be used.
7.
If only 2 valid symptom diary days are available prior to a clinic visit, data from 
the 2 days will be used to calculate the average daily normalized "off" time.
8.
If only one valid symptom diary day is available the average daily from the 
previous visit will be averaged with the daily normalized "off" time from the 
one valid diary day.
9.
Subjects that do not have any valid symptom diary days for a visit or who are 
completely missing a visit will have the average daily normalized "off" time set to 
missing for that visit.
The change from baseline in average daily normalized "on" time with troublesome 
dyskinesia, normalized "on" time with non-troublesome dyskinesia, and normalized "on" 
time without dyskinesia will be calculated for each subject using the 3 diary days prior to 
the visit and the same strategy employed for the calculation of normalized "off" time.  
Normalized "on" time without troublesome dyskinesia will be calculated for each PD 
Diary as the sum of normalized "on" time without dyskinesia and normalized "on" time 
with non-troublesome dyskinesia.
8.4.2
Unified Parkinson's Disease Rating Scale (UPDRS)
The UPDRS is an Investigator-used rating tool to follow the longitudinal course of PD.  It 
is made up of the following sections:  I) Mentation, Behavior, and Mood; II) Activities of 
Daily Living; III) Motor Examinations; IV) Complications of Therapy sections (including 
Dyskinesias); and V) Modified Hoehn and Yahr Staging, as well as the Schwab and 
 


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England Activities Of Daily Living Scale.  These are evaluated by physical examination 
and observation.  Some sections require multiple grades assigned to each extremity.
●
The Part I sub-score is the sum of the answers to the 4 questions that comprise 
Part I, each of which are measured on a 5-point scale (0 – 4).  The Part I score 
will range from 0 – 16.  No missing answers will be imputed so the Part I score 
will be missing if any of the answers are missing.
●
The Part II sub-score is the sum of the answers to the 13 questions that 
comprise Part II, each of which are measured on a 5-point scale (0 – 4).  The 
Part II score will range from 0 – 52.  The UPDRS Part II score will be 
calculated as long as at least 12 questions have been answered.  If 1 answer is 
missing the Part II score will be calculated by multiplying the sum of questions 
answered by the ratio of the total number of Part II questions to the number of 
questions answered.
●
UPDRS Part III consists of 14 questions.  Questions 20 – 26 are multi-part 
questions in that they are evaluated separately for multiple body parts.  For 
example, Question 24, related to hand movements, is assessed separately for 
the left and right hand.  Counting each of these assessments leads to a total of 
27 answers for Part III.  The Part III sub-score is the sum of the 27 answers 
provided to the 14 Part III questions, each of which is measured on a 5-point 
scale (0 – 4).  The Part III score will range from 0 – 108.  The UPDRS Part III 
score will be calculated as long as at least 23 answers have been recorded.  If 
4 or fewer answers are missing the Part II score will be calculated by 
multiplying the sum of the answers provided by the ratio of the total number of 
Part III answers possible (27) to the number of answers provided.
●
The total score is the sum of the responses to the 31 questions (44 answers) 
that comprise Parts I – III of the scale.  The total score ranges from 0 – 176 
with 176 representing the worst (total) disability, and 0 no disability.  The 
UPDRS Total score will be calculated as long as 38 answers have been 
recorded.  If 6 or fewer answers are missing the Total score will be calculated 
by multiplying the sum of answers provided by the ratio of the total number of 
answers possible (44) to the number of answers provided.
●
The Part IV Score is the sum of the answers to the 11 questions that comprise 
Part IV, 4 of which are measured on a 5-point scale (0 – 4) and 7 which are 
 


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measured on a 2-point scale (0 – 1).  The Part IV score will range from 0 – 23.  
The UPDRS Part IV score will be calculated as long as at least 10 questions 
have been answered.  If 1 answer (i.e., < 15%) is missing the Part IV score will 
be calculated by multiplying the sum of questions answered by the ratio of the 
total number of Part IV questions to the number of questions answered.
●
Additionally, Questions 32, 33, and 34 on UPDRS Part IV will be totaled to 
evaluate dyskinesias.  Each of these questions is measured on a 5-point scale 
(0 – 4).  The Part IV dyskinesia score ranges from 0 – 12.  No missing answers 
will be imputed so the Part IV score will be missing if any of the answers are 
missing.
8.4.3
Clinical Global Impression – Improvement (CGI-I)
The CGI-I is a global assessment by the Investigator of the change in clinical status since 
the start of treatment.  The CGI-I ratings are as follows:
1 = very much improved
2 = much improved
3 = minimally improved
4 = no change
5 = minimally worse
6 = much worse
7 = very much worse
8.4.4
Parkinson's Disease Questionnaire (PDQ-39)
The PDQ-39 is a disease-specific, instrument designed to measure aspects of health that 
are relevant to subjects with PD, and which may not be included in general health status 
questionnaires.  The PDQ-39 is a self-administered questionnaire that comprises 39 items 
addressing the following eight domains of health that subjects consider to be adversely 
affected by the disease:
●
Mobility (e.g., fear of falling when walking) – 10 questions
 


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●
Activities of daily living (e.g., difficulty cutting food) – 6 questions
●
Emotional well-being (e.g., feelings of isolation) – 6 questions
●
Stigma (e.g., social embarrassment) – 4 questions
●
Social support – 3 questions
●
Cognition – 4 questions
●
Communication – 3 questions
●
Bodily discomfort – 3 questions
Each question is answered on the following 5-point scale:  0 = Never, 1 = Occasionally, 
2 = Sometimes, 3 = Often, 4 = Always or Cannot Do At All.  The PDQ-39 is scored on a 
scale of 0 to 100, where lower scores indicate a better perceived health status.  Higher 
scores are consistently associated with the more severe symptoms of the disease such as 
tremor and stiffness.  The domain scores are calculated by first summing the answers to 
the questions in the domain.  The sum is divided by the highest score possible 
(i.e., number of question multiplied by 4) and the quotient is multiplied by 100 to put the 
score on a scale from 0 to 100.  The Social Support domain has 1 question that cannot be 
answered if the subject does not have a spouse or partner.  If the subject does not have a 
spouse or partner, the domain score is calculated as if the domain only had two questions.  
The PDQ-39 summary index (PDQ-39SI) is the sum of all answers divided by the highest 
score possible (i.e., number of answers multiplied by 4) which is multiplied by 100 to put 
the score on a 0 to 100 scale.  The domain scores will only be calculated if all of the 
questions are answered.  The PDQ-39SI will be calculated as long as no more than 15% 
(5) of the answers are missing.  This enables calculation of the PDQ-39SI even if one or 
more of the domain scores are not calculated.  The highest score possible will be adjusted 
based on the number of answers provided.
8.5
Safety Analysis Variables
8.5.1
Adverse Events
Adverse event (AE) Investigator terms are assigned to a Lowest Level Term (LLT) and a 
Preferred Term (PT) and will be classified by High Level Term (HLT), High Level Group 
 


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Term (HLGT) to one System Organ Class (SOC), namely the primary SOC, according to 
the MedDRA thesaurus, Version 14.0.
AE Investigator terms that are related to procedural or device complications may also 
have a secondary coding.  For example, consider the verbatim term "Worsening of 
Parkinson's disease due to PEG-J dislocation."  This AE can be coded as follows:
Primary Coding –
●
Lower Level Term:   PARKINSONISM AGGRAVATED'
●
Preferred Term:  'PARKINSONISM'
●
System Organ Class:  'NERVOUS SYSTEM DISORDERS'
Secondary Coding –
●
Lower Level Term:  'DEVICE DISLOCATION'
●
Preferred Term:  'DEVICE DISLOCATION'
●
System Organ Class:  'INJURY, POISONING AND PROCEDURAL
COMPLICATIONS'
AE summaries will include the primary as well as the secondary coding.
A detailed description of each AE includes:
●
The start and stop date of the event or "Ongoing" at the end of the study.
●
Severity (categorized as "Mild," "Moderate" or "Severe").  If severity is 
missing it will be regarded as "Severe."
●
Relationship to the investigational therapeutic system (categorized as 
"Unrelated," "Unlikely," "Possible" or "Probable").
●
Action taken with investigational study medication:
○
Drug discontinued.
○
Drug interrupted.
○
Dosage reduced.
 


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○
Dosage increased.
○
None/not applicable.
●
Outcome of event, which is defined as any one of the following:
○
Recovered/Resolved.
○
Recovered/Resolved with Sequelae.
○
Fatal.
○
Unknown.
If an adverse event is "Ongoing," the Outcome will be blank.
●
Serious, categorized as "Yes" or "No."
●
Concomitant treatment/therapy introduced, categorized as "Yes" or "No."
●
Led to study termination, categorized as "Yes" or "No."
Missing and/or incomplete dates for AEs are imputed in a manner resulting in the earliest 
onset within the Treatment Period and the longest duration.  However, the Stop Date will 
not be imputed if the event is reported as "Ongoing."
Technically, this will be done as follows:
For a missing/incomplete start date the minimum of the following will be imputed:
●
The maximum of the earliest possible start date and the date of 
first administration of investigational study drug
●
The latest possible start date
●
The latest possible stop date
For a missing/incomplete stop date the maximum of the following will be imputed:
●
The minimum of the latest possible stop date and the date of last 
administration of investigational study drug
●
The earliest possible stop date
●
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Here, the earliest (latest) possible date is defined as:
●
The date itself if it is possible
●
The date of the first (last) day of the month, if month and year are available but 
the day is missing
●
The date of the first (last) day of the year, if year is available but day and 
month are missing
●
A very early (late) date, for example, 01JAN1000 (01JAN3000), if the date is 
completely missing
From this data the following will be determined and used for presentation in the 
applicable tables and listings:
●
Treatment-Emergent Adverse Events (TEAEs):  Defined as AEs which started 
on or after the Date of the First 3005 LCIG Infusion and within 30 days of the 
Date of the Last 3005 PEG-J Exposure.  
●
Treatment-Emergent Serious Adverse Events (TESAEs):  Defined as TEAEs 
regarded by the Investigator as Serious.
●
TEAEs that are at least possibly related to the therapeutic system:  Defined as 
TEAEs assessed as having a "Possible" or "Probable" relationship to the 
investigational therapeutic system and includes those events where the 
relationship is missing.
●
Severe TEAEs:  Defined as TEAEs assessed as being "Severe" in intensity and 
includes those events where the severity is missing.
●
TEAEs that led to premature discontinuation:  Selected as those events where:  
"Led to Study Termination" is indicated as "Yes."
●
TEAEs with fatal outcome as reported on the "Adverse events" CRF.
●
TEAEs in the following categories have been defined as TEAEs of special 
interest:
○
Procedure and device associated events
○
Polyneuropathy (broad search as well as narrow search)
○
Weight loss
 


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○
Cardiovascular fatalities
○
Respiratory tract aspiration including aspiration pneumonia/pneumonitis
TEAEs are included in a category of special interest based on their PT and, in the case of 
cardiovascular fatalities, their outcome.  The list of PT's assigned to each category is 
included as Appendix 12.4.  Only TEAEs where an outcome of "Fatal" has been reported 
on the "Adverse Event" CRF are to be included in the category of cardiovascular 
fatalities.  All events with PT's other than those assigned to the procedure and device 
associated AESI category will be included in summaries of events that are not procedure 
and device related. 
The percentage of each of the aforementioned AE types will be determined as the number 
of subjects with at least one mention of the AE type relative to the number of subjects at 
risk.  A subject will be considered at risk if the subject is in the Safety subject sample.
In addition to the aforementioned AE types, AEs reported by the Investigator as related to 
device complications will also be summarized.  Device complications are captured in the 
DE raw data panel and associated AEs are captured in the AE raw data panel.  
Investigators link the AEs that are related to device complications by entering an AE 
number in the DE raw data panel.
The incidence and prevalence of TEAEs during each 3005 Treatment Year will be 
summarized using the study day intervals described in Section 6.4.9.  AE start days and 
Treatment Period end days will be calculated relative to the start of 3005 LCIG infusion 
(RFSTDTN) as follows:
AE Start Day = (AE Start Date – Date of First 3005 LCIG Infusion) + 1
Treatment Period End Day = ([Date of Last 3005 PEG-J Exposure + 30 Days] –
First Date of 3005 LCIG Infusion) + 1
For summaries of incidence, the count (and numerator for percentage calculations) will be 
the number of subjects who had their first treatment-emergent occurrence of the PT start 
 


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within the study day range for the 3005 Treatment Year.  Each subject will be counted at 
most once within each SOC and PT.
For summaries of prevalence, the count (and numerator for percentage calculations) will 
be the number of subjects who had a treatment-emergent occurrence of the PT start within 
the study day range for the 3005 Treatment Year or who had an earlier treatment-
emergent occurrence of the PT that had not ended prior to the start of the study day range 
for the 3005 Treatment Year. 
The denominator for both incidence and prevalence percentage calculations will include 
all subjects whose Treatment Period End Day is within or greater than the study day range 
for the 3005 Treatment Year.
8.5.2
Safety Laboratory Data
Special tests for vitamin deficiencies (Folic Acid, Vitamin B6, Vitamin B12, 
Methylmalonic Acid (MMA), and Homocysteine) were added to the schedule of 
assessments (Appendix 12.1) with Protocol Amendment 2.  Additional clinical laboratory 
evaluations are to be performed as an element of routine care and are done as a subject's 
condition mandates.  The final visit is the only study visit at which they are one of the 
scheduled assessments.  Abnormal lab results are to be reported, including the 
Investigator's opinion of whether they are clinically significant.  Clinically significant 
laboratory results are also to be reported as an AE.
Potentially clinically significant (PCS) laboratory values will be identified.  A laboratory 
value will be considered potentially clinically significant if it satisfies the criteria 
presented in Table 4 and is also more extreme than the subject's corresponding baseline 
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Table 4.
Criteria for Identification of Potentially Clinically Significant (PCS) 
Laboratory Values
Variable (Synonyms)
Medical Condition
S.I. Units
Unit
Lower 
Limit
Upper 
Limit
Blood Biochemistry
Alanine aminotransferase 
(ALT, GPT, SGPT)
Liver toxicity
U/L
NA
> 3 × ULN
Alkaline phosphatase (ALP)
Liver toxicity
U/L
NA
> 400 U/L
Aspartate aminotransferase 
(AST, GOT, SGOT)
Liver toxicity
U/L
NA
> 3 × ULN
Bilirubin (Total)
Liver toxicity
mcmol/L
NA
> 2 × ULN
Creatinine
mcmol/L
NA
> 177
Creatine phosphokinase (CPK)
Myocardial infarction/ 
Muscular dystrophy
U/L
NA
> 3 × ULN
Lactate dehydrogenase (LDH)
U/L
NA
> 3 × ULN
Blood urea nitrogen (BUN)
mmol/L
NA
> 10.8
Uric acid
Female
mcmol/L
NA
> 500
Male
mcmol/L
NA
> 590
Albumin
g/L
< 25
> 70
Calcium (Total)
mmol/L
< 1.75
> 3.0
Total cholesterol 
mmol/L
NA
> 12.9
Gamma glutamyl-transferase (GGT)
U/L
NA
> 3 × ULN
Glucose
mmol/L
< 2.78
> 16.0
Potassium
mmol/L
< 3.0
> 6.0
Protein (Total)
g/L
< 45
NA
Sodium
mmol/L
< 126
> 156
Triglycerides 
mmol/L
NA
> 5.6
 


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Table 4.
Criteria for Identification of Potentially Clinically Significant (PCS) 
Laboratory Values (Continued)
Variable (Synonyms)
Medical Condition
S.I. Units
Unit
Lower 
Limit
Upper 
Limit
Blood Biochemistry (continued)
Hematology
Eosinophils
%
NA
> 10
Hematocrit (Ejection 
Volume
Fraction)
Female
%
< 30
NA
Male
%
< 34
NA
Hemoglobin 
Female
g/L
< 90
NA
Male
g/L
< 100
NA
Leukocytes (WBC)
109/L
< 2.8
> 16.0
Neutrophils, abs
109/L
< 1.2
NA
Thrombocytes (Platelets)
109/L
< 95
> 700
Erythocytes (RBC) 
Female
1012/L
< 2.0
NA
Male
1012/L
< 2.5
NA
Lymphocytes
%
NA
> 80
Lymphocytes, abs
109/L
< 0.75
NA
Mean corpuscular volume (MCV)
fL
< 60
> 120
Monocytes
%
NA
> 30
8.5.3
Vital Signs and Weight
The measured vital signs include:
●
Weight (kg).
●
Body Temperature (degrees Celsius) and Route of Measurement.
●
Systolic Blood Pressure (SBP [mmHg]), supine and standing.
●
Diastolic Blood Pressure (DBP [mmHg]), supine and standing.
●
Pulse Rate (bpm), supine and standing.
 


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The following orthostatic vital signs will be calculated based on measurements in the 
supine and standing positions:
●
Orthostatic SBP (mmHg) = Standing SBP – Supine SBP
●
Orthostatic DBP (mmHg) = Standing DBP – Supine SBP
●
Orthostatic Pulse Rate (bpm) = Standing Pulse Rate – Supine Pulse Rate
See Section 8.2.2 (Other Baseline Characteristics) for the derivations and conversions of 
the aforementioned variables.  At each scheduled visit, preferably by the same observer, 
supine and standing SBP, DBP, and pulse rate will be measured using the same arm after 
the subject has been in the position for 2 minutes.
Potentially clinically significant (PCS) vital signs values will be identified.  A vital sign 
value will be considered potentially clinically significant if it satisfies the criteria 
presented in Table 5 and is also more extreme than the subject's corresponding baseline 
value.
Table 5.
Criteria for Identification of Potentially Clinically Significant (PCS) 
Vital Sign and Weight Values
Variable
Unit
Very Low (VL)
Very High (VH)
SBPa
mmHg
Value ≤ 90 and > 30 decrease from 
Baseline
Value ≥ 180 and > 40 increase 
from Baseline
DBPa
mmHg
Value ≤ 50 and > 30 decrease from 
Baseline
Value ≥ 105 and > 30 increase 
from Baseline
Pulse Ratea
bpm
Value ≤ 50 and > 30 decrease from 
Baseline
Value ≥ 120 and > 30 increase 
from Baseline
Temperature
°C
NA
Value ≥ 38.3 and ≥ 1.1 increase 
from Baseline
Orthostatic SBP 
(Hypotension)
mmHg
Decrease of ≥ 30 in SBP (supine to 
standing)
NA
Orthostatic DBP 
(Hypotension)
mmHg
Decrease of ≥ 20 in DBP (supine 
to standing)
NA
Weight 
kg
Decrease of ≥ 7% from Baseline
Increase of ≥ 7% from Baseline
a.
Both for supine and standing.
 


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8.5.4
Electrocardiogram (ECG) Data
In Study 3005, single standard 12-lead electrocardiograms (ECGs) are to be performed as 
an element of routine care and are done as a subject's condition mandates.  The final visit 
is the only study visit at which an ECG is one of the scheduled assessments.  All ECGs 
are to be reviewed by a local reader, who assesses them as "Normal," "Abnormal, not 
clinically significant," "Abnormal, clinically significant" or "Unknown."  Clinically 
significant abnormalities in the ECG are to be reported as an AE and the subject's ECG is 
to be repeated at medically appropriate intervals until it stabilizes or returns to acceptable 
levels.  Due to the limited data collected, ECG results and interpretations will be 
presented as a listing but will not be summarized.
8.5.5
Other Safety Analyses
Other safety data, not previously discussed, include:
●
Complications with infusion device
●
PEG tube and J tube replacements and average duration
●
Sleep attacks
●
Minnesota Impulsive Disorders Interview (MIDI)
●
Columbia Suicide Severity Rating Scale (C-SSDRS)
●
Melanoma check
●
Neurological examination
8.5.5.1
Complications with Infusion Device
For each complication related to the infusion device (i.e., tubing kinks, tubing displaced, 
tubing connector problems, and pump technical difficulties) the following data will be 
collected in addition to a description of the complication.
●
Incident start and stop date
●
Type of complication
○
Pump complication
 


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○
Intestinal tube complication
○
PEG-J complication
○
Stoma complication
○
Other complication
●
Action taken
○
No action taken
○
Reposition of tube with surgery
○
Reposition of tube without surgery
○
Pump replaced
○
Medication treatment interrupted
○
Medication treatment stopped
○
Other
●
Did this complication result in an AE? ("Yes" or "No")
●
For complications that resulted in an AE, the AE number(s)
Each device complication will be assigned to a Preferred Term (PT), according to the 
MedDRA thesaurus, Version 14.0.
The percentage of subjects with a device complication will be determined as the number 
of subjects with at least one device complication relative to the number of subjects at risk.  
A subject will be considered at risk if the subject is in the Safety subject sample.  
Summaries of device complications by action taken will exclude complications where the 
response for action taken is "No action taken."
The incidence of device complications during each 3005 Treatment Year will be 
summarized using the study day intervals described in Section 6.4.9.  Device complication 
start days and Treatment Period end days will be calculated relative to the start of 3005 
LCIG infusion (RFSTDTN) as follows:
Device Complication Start Day = (Device Complication Start Date – Date of 
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Treatment Period End Day = ([Date of Last 3005 PEG-J Exposure + 30 Days] –
First Date of 3005 LCIG Infusion) + 1
The count (and numerator for percentage calculations) will be the number of subjects who 
had their first occurrence of the PT start within the study day range for the 3005 
Treatment Year.  Each subject will be counted at most once within each SOC and PT.
The denominator for percentage calculations will include all subjects whose Treatment 
Period End Day is within or greater than the study day range for the 3005 Treatment Year.
8.5.5.2
PEG Tube and J Tube Replacements and Average Duration
The date of each PEG tube and J tube placement and removal is recorded on the Device 
Information eCRF.  The number of PEG tube replacements and the number of J tube 
replacements overall and by 3005 Treatment Year will be summarized.
The number of PEG tube and J tube replacements during each 3005 Treatment Year will 
be summarized using the study day intervals described in Section 6.4.9.  Tube 
replacement days and Treatment Period end days will be calculated relative to the start of 
3005 LCIG infusion (RFSTDTN) as follows:
Tube Replacement Day = (Tube Placement Date – Date of First 3005 LCIG 
Infusion) +1
Treatment Period End Day = ([Date of Last 3005 PEG-J Exposure + 30 Days] –
First Date of 3005 LCIG Infusion) +1
The count (and numerator for percentage calculations) will be the number of subjects who 
had one or more PEG (or J) tube replacements within the study day range for the 3005 
Treatment Year.  Each subject will be counted at most once for each 3005 Treatment 
Year.
The denominator for percentage calculations will include all subjects whose Treatment 
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As previously described, Study 3005 is an extension of the previous Studies 3001, 3002, 
3003, and 3004.  The number of PEG tube and J tube replacements in these previous 
studies will be retrieved from the relevant study databases and will be summarized.
The average PEG tube and J tube duration (time in place) during Study 3005 will be 
summarized.  For each tube the duration  will be calculated as the tube removal date – the 
tube placement date +1.  The average PEG tube and average J tube duration for each 
subject will then be calculated as the mean of all PEG (J-tube) tubes the subject had 
exposure to during the study.  For tubes already in place at the start of the study (missing 
placement date), the placement date will be imputed as the date of the first 3005 LCIG 
infusion (as defined in Section 6.4.1).  For tubes remaining in place (missing removal 
date), the removal date will be imputed as the date of the last 3005 PEG-J exposure (as 
defined in Section 6.4.1).  Due to the imputation of placement and removal dates, the 
3005 tube duration will be interpreted as the minimal amount of time the tube was in 
place.
8.5.5.3
Sleep Attacks
In order to prospectively monitor for the possible development of sleep attacks the 
following questions will be asked of subjects at each visit:
Since your last visit (or time this question was asked), have you experienced any 
events in which you fell asleep suddenly or unexpectedly, including while engaged 
in some activity (e.g., eating/drinking, speaking, or driving) or at rest, with or 
without any previous warning of sleepiness?
●
If yes, what specifically happened?
●
How many times did you experience such events?
●
What were you doing at the time of each event?
●
Prior to each event did you experience any sleepiness or drowsiness?  If yes, 
please explain/clarify.
●
How long did each event last?
 


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●
Did you suffer any "bad" outcome/problem from each falling asleep event?
The summary of sleep attacks will include the incidence of subjects with sleep attacks and 
the incidence of subjects with "bad outcomes" at Baseline and at any time during the 
Treatment Period.  Summaries of sleep attacks by visit will be considered if the initial 
results indicate a high incidence of subjects with sleep attacks.
8.5.5.4
Minnesota Impulsive Disorders Interview (MIDI)
In order to monitor for the development of intense impulsive behavior the Minnesota 
Impulsive Disorder Interview (MIDI) will be administered at each visit.  The MIDI is a 
semi-structured clinical interview assessing pathological gambling, trichotillomania, 
kleptomania, pyromania, intermittent explosive disorder, compulsive buying, and 
compulsive sexual behavior.  A subject's MIDI screen is positive for a disorder if:
●
Buying Disorder:  Positive screen if the subject answers "yes" to 1a, 2a, 3a, 
and 4a
●
Kleptomania:  Positive screen if the subject answers "yes" to 1a, 2a, 3a, and 4a
●
Trichotillomania:  Positive screen if the subject answers "yes" to 1, 3, 4a, 5, 
and 6
●
Intermittent Explosive Disorder:  Positive screen if the subject answers "yes"
to 1a, 1b, 1c, and 1d; in addition, the subject must answer "no" to 1f
●
Pyromania:  Positive screen if the subject answers "yes" to 1a, 2, 3, 4, and 5; in 
addition, the subject must answer "no" to 1b, 1c, 1d, and 1e
●
Pathological Gambling:  Positive screen if the subject answers "yes" to 1, and 
to at least 5 of the rest of the questions
●
Compulsive Sexual Behavior:  Positive screen if the subject answers "yes" to 
1, 2a, 3a, or 4a
The incidence of subjects who report intense impulsive behavior at Baseline and at any 
time during the Treatment Period will be provided.  Summaries of MIDI assessments by 
 


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visit will be considered if the initial results indicate a high incidence of subjects with 
intense impulsive behavior.
8.5.5.5
Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS)5 is a systematically administered 
instrument developed to track suicidal adverse events across a treatment study.  It was 
added to the flowchart of study assessments (Appendix 12.1.3) with Protocol 
Amendment 3.  At each study visit, the C-SSRS will collect experience since the last visit.  
The incidence of subjects with affirmative responses on the C-SSRS at any time during 
the Treatment Period will be provided.
Each summary will include the number and percentage of subjects with one or more 
affirmative responses to each of the 5 suicidal ideation questions, each of the 6 suicidal 
behavior questions, any of the 5 suicidal ideation questions, any of the 6 suicidal behavior 
questions, any suicidal ideation or behavior question, and the non-suicidal self-injurious 
behavior question. 
8.5.5.6
Melanoma Check
A comprehensive assessment for the presence of melanoma must be performed at least 
once a year by a dermatologist experienced with the diagnosis of the condition.  If a 
suspicious lesion is present, a biopsy should be obtained for proper diagnosis.  Subjects 
who have a melanoma present at the start of the study, or who develop one during the 
course of the study should be discontinued from participation and referred for proper 
follow-up care.
8.5.5.7
Neurological Examination
At each of the scheduled visits indicated in the flowchart of study assessments a 
neurological examination will be performed including light touch and pinprick sensation, 
vibratory sensation, deep tendon reflexes, and strength assessments.  Any abnormalities or 
symptoms identified will be reported as adverse events.
 


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9.0
Statistical Analysis
This section will indicate how the statistical analysis will be performed on the basis of the 
conventions, definitions and techniques that are described in Section 6.0 through 
Section 8.0.  To each standard table (T), listing (L) or figure (F) a unique code is assigned 
which is used as a reference in the SAP and indicated on the appropriate 
table/listing/figure template.  For example, a demographics table is assigned the unique 
code of DMT001, where DM refers to the clinical domain (Demographic Data), 
T indicates that it is a table and 001 indicates that it is the first table in the DM set of 
tables.  Tables, listings and figures that are referred to are listed in the Appendices, 
Section 12.2 and Section 12.3.
9.1
Subject Disposition
Subject disposition (DS) will be summarized for all centers/countries combined by means 
of the default summary statistics described in Section 6.0 (General Definitions, Methods, 
Naming Conventions and Data Handling).
Subject Samples:
Tables
All subjects consented and Efficacy Sample 
US Subset
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
DS
 


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Standard Presentations
DST001
The primary reason for premature discontinuation after consent, as 
recorded on the "Study Termination" form, will be presented.  The primary 
reason for premature discontinuation includes:
●
Adverse Event
●
Lack of Efficacy
●
Lost to Follow-up
●
Withdrew Consent
●
Administrative
●
Protocol Violation
The number of subjects who have completed the study and the number 
whose participation in the study is ongoing will also be presented.  The 
percentage of subjects will be calculated relative to the number of 
consenting subjects.
DST002
Subject validity/subject sample status will be summarized with the reason 
for exclusion from the Safety sample.  The only reason for exclusion from 
the safety sample will be that the subject did not infuse any study 
medication after providing informed consent.
DST003
The number and percentage of subjects prematurely discontinuing in each 
3005 treatment year will be summarized.
Standard subject data listings include:
DSL001
A listing of subjects who prematurely discontinued their participation in the 
study prior to receiving 3005 LCIG.
 


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DSL002
A listing of subjects who discontinued participation after receiving 3005 
LCIG will be presented.  The relative treatment day of last contact with the 
subject and the last day of 3005 LCIG infusion, as captured on the "Study 
Termination" CRF form will be calculated as:
●
Relative Treatment Day of Last Contact = (Date of Last Contact –
Date of First 3005 LCIG Infusion) + 1
●
Relative Treatment Day of Last 3005 LCIG Infusion = (Date of 
Last 3005 LCIG Infusion – Date of First 3005 LCIG Infusion) + 1
DSL003
Exclusion from the Safety subject sample together with the reason(s) for 
exclusion will be presented.  This listing will include all possible reasons 
for exclusion per subject.
Study Specific Presentations
Not applicable.
9.2
Major Protocol Deviations
Major protocol deviations (DV) will be summarized for all centers/countries combined.
Subject Samples:
Tables
Safety sample
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
DV
Standard Presentations
DVT001
The number of unique subjects presenting with at least one major protocol 
deviation will be presented.  In addition, the number and percentage of 
subjects allocated to treatment in each major protocol deviation category 
will be presented.  Subjects may have more than one major protocol 
deviation.
 


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Standard subject data listings include:
DVL001
A by-subject listing of all subjects with one or more major protocol 
deviations will be presented.
Study Specific Presentations
Not applicable.
9.3
Inclusion/Exclusion Criteria
Only the exceptions are to be listed, that is, subjects with a response to the Inclusion 
Criteria of "No" and/or subjects with a response to the Exclusion Criteria of "Yes."  
Subjects with a missing response to Inclusion/Exclusion Criteria will also be presented.
Subject Samples:
Tables
Not applicable
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
IE
Standard Presentations
The response (Yes/No) per subject with at least one exception to each of the study specific 
inclusion/exclusion criteria, will be presented as a subject data listing as follows:
IEL001
Listing of all Inclusion Criteria including a text description of each 
criterion and the response as either "Yes" or "No" for those subjects with at 
least one exception.
IEL002
Listing of all Exclusion Criteria including a text description of each 
criterion and the response as either "Yes" or "No" for those subjects with at 
least one exception.
 


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Study Specific Presentations
Not applicable.
9.4
Demographic Data and Other Baseline Characteristics
9.4.1
Demographic Data
Subject demographic data (DM), described below, will be summarized and presented for 
observed data only.  All missing data will be presented as part of a missing category, if 
appropriate.
Subject Samples:
Tables
Safety sample and US Subset
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
DM
Standard Presentations
DMT001
Qualitative demographic data, presented by means of default summary 
statistics, includes:
●
Gender:  Male or Female.
●
Race:  American Indian or Alaska Native, Asian, Black of 
African Heritage or African American, Native Hawaiian or Other 
Pacific Islander, White.  For each subject one or more race 
categories can be selected.
●
Ethnicity:  Hispanic or Non-Hispanic. 
●
Age:  < 65, ≥ 65.
●
Country
Quantitative demographic data includes:
●
Age (years) presented by default summary statistics.
 


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Standard subject data listings include:
DML001
Standard demographic data will be presented.  Missing data will not be 
imputed for the listing.  An incomplete date will be presented, for 
example, as – Jan 1980, as originally entered in the CRF.  The relative 
day of assessment will be calculated relative to the start of the 3005 
LCIG infusion (RFSTDTN) and will be presented for those subjects who 
received 3005 LCIG infusion.
Study Specific Presentations
Not applicable.
9.4.2
Other Baseline Characteristics
Default summary statistics, described in Section 6.0 (General Definitions, Methods, 
Naming Conventions and Data Handling), of the baseline subject characteristics will be 
presented for all countries/centers combined.
Subject Samples:
Tables
Safety sample and US Subset
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
SC
 


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Standard Presentations
SCT001
Other subject characteristics (SC) include the following vital signs:
●
Systolic Blood Pressure (SBP [mmHg]), supine, standing, and 
orthostatic
●
Diastolic Blood Pressure (DBP [mmHg]), supine, standing, and 
orthostatic
●
Pulse rate (bpm), supine, standing, and orthostatic
●
Height (m)
●
Weight (kg), overall and by gender
●
BMI (kg/m2)
●
Body temperature (degrees Celsius)
●
Route of measurement
Standard subject data listings include:
SCL001
The aforementioned vital signs data will be presented by subject.  The 
relative day of the assessment will be calculated relative to the start of 
3005 LCIG infusion (RFSTDTN) and will be presented for those 
subjects who received 3005 LCIG infusion.
Study Specific Presentations
SCT002
Other subject characteristics include the following assessments 
collected during the Initial Screening Period:
●
Duration in years since the first diagnosis of PD 
●
Diagnosis of bradykinesia (slowness of initiation of voluntary 
movement with progressive reduction in speed and amplitude of 
repetitive actions)
●
Diagnosis of muscular rigidity
●
Diagnosis of 4 – 6 Hz resting tremor
●
Diagnosis of postural instability not caused by primary visual, 
vestibular, cerebellar or proprioceptive dysfunction
 


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SCT003
PD medications that were started during the previous study and 
continue to be used by the subject will be summarized.  The primary 
ATC class (e.g., Dopa and Dopa Derivatives, Dopamine Agonists, 
COMT Inhibitors, etc.) will be used to group similar medications.  
Subjects will be categorized according to the number of medication 
classes used (i.e., 1, 2, 3, or > 3 PD medication classes).  Within each 
group of subjects, the number of subjects using each medication type 
will be summarized using default summary statistics.  The percentage 
of subjects taking 1, 2, 3, or > 3 PD medications is calculated relative to 
the total number of subjects considered valid for the specific subject 
sample, that is, Safety subject sample.  The percentage of subjects 
taking a medication in a specific ATC class is calculated relative to the 
number of subjects in the 1, 2, 3, > 3 PD medication subgroups.
Study Specific subject data listings include:
SCL002
A listing of the date and duration of diagnosis as well as results of the 
'Diagnosis of Idiopathic Parkinson's Disease' according to the modified 
UKPDS brain bank criteria will be provided.
SCL003
By-subject and within-subject by ascending start date/relative start day 
of PD medication use.  In SCL003 the relative start and stop day of PD 
medication use will be calculated relative to the first 3005 LCIG 
infusion and will be presented for those subjects who were allocated to 
treatment and received at least one dose of investigational study 
medication.  If the medication is "Ongoing" it will be indicated as such 
in the listing and the relative stop day will not be calculated.  Only 
original dates will be presented in the listing even though the relative 
day may be based on an imputed date.
SCL004
A listing of the relevant WHO-DD coding information, sorted in the 
same way as SCL003 will also be provided.
9.5
Medical and Neurological History
Subject Samples:
Tables
Safety sample
Listings
All subjects consented
Figures
Not applicable
 


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Subgroups:
Not applicable
Abbreviation:
MH
Standard Presentations
Medical history findings collected on the Medical History and Neurological History CRFs 
during the Initial Screening Period will be combined and summarized as follows:
MHT001
The number of subjects with at least one medical or neurological history 
finding will be presented by default summary statistics, where the 
percentage of subjects is calculated relative to the total number of 
subjects considered valid for the specific subject sample, for example, 
Safety subject sample.  In addition, the number of subjects with at least 
one medical or neurological history finding within each primary SOC and 
PT, will be presented.
Standard subject data listings include:
MHL001
Medical and neurological history findings will be presented by-subject 
and within-subject by ascending order of start date of each medical 
history.
MHL002
A listing of the relevant MedDRA coding information, sorted in the same 
way as MHL001 will also be provided.
Study Specific Presentations
Not applicable.
9.6
Concomitant Medication
Concomitant medication will be presented as the number and percentage of subjects 
taking concomitant medication according to WHO-DD, 01 March 2011, primary ATC 
third level subgroup and generic name (corresponds to the first 6 digits of the 11-digit 
WHO-DD code).  For the standard presentation, percentages will be calculated relative to 
the number of subjects considered valid for the Safety sample.
 


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Subject Samples:
Tables
Safety sample and US Subset
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
CM
Standard Presentations
Concomitant medication assigned to the Treatment Period will be summarized as follows:
CMT001
The number of subjects with at least one concomitant medication use in 
the Treatment Period will be presented by default summary statistics, 
where the percentage of subjects is calculated relative to the total number 
of subjects considered valid for the specific subject sample, that is, Safety 
subject sample.  In addition, the number of subjects with at least 
one concomitant medication use within each ATC third level subgroup 
and generic name will be presented.  The ATC third level subgroups are 
to be ordered alphabetically/numerically by ATC code and within ATC 
third level subgroup alphabetically by generic name.
All medications entered on the "Concomitant Medication" CRF form will be presented in 
subject data listings as follows:
CML001
By-subject and within-subject by ascending start date/relative start day of 
medication use.  In CML001 the relative start and stop day of 
concomitant medication use will be calculated relative to the start of the 
first infusion and will be presented for those subjects who were allocated 
to treatment and received at least one dose of investigational study 
medication.  If the concomitant medication is "Ongoing" it will be 
indicated as such in the listing and the relative stop day will not be 
calculated.  Only original dates will be presented in the listing even 
though the relative day may be based on an imputed date.
CML002
A listing of the relevant WHO-DD coding information, sorted in the 
same way as CML001 will also be provided.
 


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Study Specific Presentations
CMT002
The number of subjects with at least one anti-parkinsonian concomitant 
medication used in the Treatment Period will be presented by time 
interval (Year 1, Year 2, Year 3, Year 4, Year 5, > Year 5) using default 
summary statistics, where the percentage of subjects is calculated relative 
to the total number of subjects considered valid for the specific subject 
sample, that is, Safety Sample during the given time interval.  In addition, 
the number of subjects with at least one concomitant medication use 
within each ATC third level subgroup and generic name will be 
presented.  The ATC third level subgroups are to be ordered 
alphabetically/numerically by ATC code and within ATC third level 
subgroup alphabetically by generic name.
9.7
Drug Accountability
Subject Samples:
Tables
Not applicable
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
DA
Standard Presentations
Not applicable.
Study Specific Presentations
The following subject data listings will be prepared:
DAL001
The number of medication cassettes dispensed and returned will be 
presented.
 


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9.8
Treatment Exposure
Subject Samples:
Tables
Safety sample and US Subset
Listings
All subjects consented
Figures
Not applicable
Subgroups:
First LCIG infusion study (3001/3002, 3003 or 3004)
Abbreviation:
EX
Standard Presentations
Not applicable.
Study Specific Presentations
EXT001
The duration of 3005 LCIG exposure, overall duration of LCIG exposure, 
duration of 3005 PEG-J exposure, and overall duration of PEG-J 
exposure will be summarized using the same table format.  These 
durations are defined in Section 6.4.1 (General Definitions) and also 
Section 8.3.2 and will be summarized using the appropriate default 
summary statistics.  The number of subjects exposed will be presented by 
yearly time intervals (Year 1, Year 2, Year 3, Year 4, Year 5, > Year 5).  
A subject will be counted within an interval if their duration of exposure 
extended into the interval for 1 or more days.  The total subject-years of 
exposure will also be presented.
EXT002
The prescribed pump settings for the morning dose and flow rate at the 
conclusion of the preceding study will be summarized using the 
appropriate default summary statistics.  The summary will not include 
subjects who enrolled in Study 3005 after completing Study 3003 
because the prescribed pump settings were not recorded in that study.
 


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EXT003
The average total daily levodopa dose at the final 3005 visit will be 
summarized with descriptive statistics for each component as well as for 
the total levodopa dose.  Each subject's total daily levodopa dose at the 
end of titration in their initial LCIG study (Studies 3001, 3002, 3003 or 
3004) will be retrieved from the relevant database.  The total daily 
levodopa dose at the end of initial titration and the change from the end 
of initial titration to final 3005 visit will be summarized with descriptive 
statistics.
EXT004
The total daily levodopa dose at the end of initial titration and the change 
from the end of initial titration to final 3005 visit will be summarized by 
subgroup for the Safety Sample – US Subset.
Subject data listings include:
EXL001
A listing of treatment exposure data, including the first and last dates of 
3005 LCIG infusion will be presented by-subject.
9.9
Efficacy Analyses
Subject Samples:
Tables
Efficacy Sample and US Subset
Listings
All subject consented 
Figures
Not applicable
Subgroups:
First LCIG infusion study (3001/3002, 3003 or 
3004), troublesome dyskinesia at initial LCIG 
infusion (< 1 hour, > 1 hour), dose of levodopa at 
initial LCIG infusion (< 1250 mg/day, 
> 1250 mg/day), and levodopa monotherapy during 
Study 3005 (yes, no)
Abbreviation:
QS
 


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Standard Presentations
QST001
The average daily normalized "off" time will be summarized at initial 
LCIG infusion, at 3005 baseline and at 3005 endpoint as well as the 
change from initial LCIG infusion to 3005 endpoint and the change from 
3005 baseline to 3005 endpoint.  Descriptive statistics (including n, 
mean, minimum, maximum and 95% confidence interval) will be 
calculated.
Statistical tests for within group changes from initial LCIG infusion and 
from 3005 baseline will be implemented using PROC UNIVARIATE.
For the UNIVARIATE the following SAS® code will be used:
PROC UNIVARIATE data = <SAS®-dataset> cibasic alpha = 0.05; 
VAR OFFTIME; 
RUN;
The same methods defined above for average daily normalized "off" time 
will also be used to analyze the following assessments:
1.
Change in average daily normalized "on" time without 
troublesome dyskinesia 
2.
Change in average daily normalized "on" time with troublesome 
dyskinesia 
3.
Change in average daily normalized "on" time with mon-
troublesome dyskinesia
4.
Change in average daily normalized "on" time without dyskinesia
5.
Change in the UPDRS total score, subscores of Parts I – IV and 
Part IV Questions 32, 33 and 34 (Dyskinesia items)
6.
Change in the PDQ-39 summary index and each domain score
Variables derived from the PD Diary and PDQ-39 will be summarized 
for the Efficacy sample and the US subset of the Efficacy sample.  
Variables derived from the UPDRS will be summarized for the US subset 
of the Efficacy sample.
QST002
The change from initial LCIG infusion to 3005 endpoint and from 
3005 baseline to 3005 endpoint will be summarized by subgroup in the 
Efficacy sample – US Subset for the PD Diary variables.
QST003
The CGI score at 3005 endpoint will be summarized using the 
appropriate default summary statistics for the Efficacy sample.
 


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Subject data listings will include:
QSL001
A listing of Parkinson's Disease Diary data by-subject and within-subject 
by visit will be presented.
QSL002
A listing of CGI-I scores by-subject and within-subject by visit will be 
presented.
QSL003
A listing of PDQ-39 responses by subject and within-subject by visit will 
be presented.
QSL004
A listing of UPDRS responses by subject and within-subject by visit will 
be presented.
9.10
Pharmacokinetic and Pharmacodynamic Analyses
No pharmacokinetic or pharmacodynamic analyses will be completed.
9.11
Analysis of Safety
9.11.1
Adverse Events
Adverse events (AEs) will be reported on a per-subject basis.  This implies that even if a 
subject reported the same event repeatedly (same event that maps to the same PT), the 
event will be counted only once.  In the latter case, the event will be assigned the worst 
severity and strongest relationship to the investigational study medication.  Except for 
summaries of prevalence, the presentation of AEs is therefore restricted to the incidence 
per subject of AEs assigned to the Treatment Period.  For summaries of prevalence over 
time, each event (all events that map to the same PT) will be counted only once per 
subject for each time period presented.
 


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Subject Samples:
Tables
Safety sample and US subset of safety sample
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Gender, age category (< 65, ≥ 65), duration of 
Parkinson's disease (< 10 years, ≥ 10 years), country
Abbreviation:
AE
Standard Presentations
Adverse events will be summarized by default summary statistics, for all centers/countries 
combined as well as for subjects enrolled at US sites.  Percentages will be calculated 
relative to the total number of subjects considered valid for the subject sample.
The following standard presentations will be produced for all TEAEs in the Safety subject 
sample.
AET001
Overview of AEs including the number of subjects with:
●
At least one TEAE.
●
At least one TEAE that is at least possibly drug-related.
●
At least one serious TEAE.
●
At least one SAE.
●
Any AE leading to death.
●
A TEAE leading to death.
●
A TEAE leading to premature discontinuation.
●
At least one severe TEAE.
AET002
Incidence of TEAEs will be presented by primary SOC and PT.  The 
primary SOCs are to be ordered alphabetically.  Within each SOC, the PT 
is also to be ordered alphabetically.
AET003
Incidence of TEAEs will be presented by PT.  SOCs will not be 
presented and PTs will be ordered by decreasing frequency of 
occurrence.
 


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AET004
Incidence of TESAEs will be presented by primary SOC and PT.  The 
primary SOCs are to be ordered alphabetically.  Within each SOC, the PT 
is also to be ordered alphabetically.
AET005
Incidence of TEAEs leading to premature discontinuation will be 
presented by primary SOC and PT.  The primary SOCs are to be ordered 
alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
AET006
For each defined category of special interest, incidence of TEAEs will be 
presented by primary SOC and PT.  The primary SOCs are to be ordered 
alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
AET007
Incidence of TEAEs by strongest relationship.  A default frequency table 
by primary SOC and PT will be presented.  The primary SOCs are to be 
ordered alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
AET008
Incidence of TEAEs that are at least possibly related to treatment will be 
presented by primary SOC and PT.  The primary SOCs are to be ordered 
alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
AET009
Incidence of TEAEs by maximum severity.  A default frequency table by 
primary SOC and PT will be presented.  The primary SOCs are to be 
ordered alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
In addition, AE data will be listed as follows:
AEL001
All AEs by-subject and within-subject by start date/relative start day of 
the adverse event.  In AEL001 the relative start and stop day of the AE 
will be calculated relative to the date of the first 3005 LCIG infusion and 
will be presented for the Safety subject sample.  If the AE is "Ongoing" it 
will be indicated as such in the listing and the relative stop day will not 
be calculated.  Only original dates will be presented in the listing even 
though the relative day may be based on an imputed date.
AEL002
A listing of the relevant MedDRA coding information will be provided as 
AEL002, sorted in the same chronological order as AEL001.
 


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AEL003
Listing of deaths.  AEL003 also includes the general demographic data 
for each subject who died (gender, age, ethnicity and race).
AEL004
Listing of SAEs.  AEL004 lists all subjects with at least one serious 
adverse event indicating whether the SAE is treatment-emergent or not.
AEL005
Listing of TEAEs leading to study termination.  AEL005 will be 
presented for those subjects valid for the Safety subject sample with at 
least one adverse event for which the question "Led to Study 
Termination" is indicated as "Yes."
AEL006
Listing of TEAEs of special interest.  A listing will be presented for each 
AE of special interest category.
Study Specific Presentations
AET010
Incidence of TEAEs that have been linked to a device complication by 
investigators through the Device Complication CRF.  A default 
frequency table by primary SOC and PT will be presented.  The primary 
SOCs are to be ordered alphabetically.  Within each SOC, the PT is also 
to be ordered alphabetically.
AET011
Incidence of TEAEs within each consecutive 3005 Treatment Year (as 
defined in Section 6.4.9) will be summarized.  A default frequency table 
by primary SOC and PT will be presented.  The primary SOCs are to be 
ordered alphabetically.  Within each SOC, the PT is also to be ordered 
alphabetically.
AET012
Incidence of TEAEs within subgroups.  A default frequency table by 
primary SOC and PT will be presented for each subgroup category.  The 
primary SOCs are to be ordered alphabetically.  Within each SOC, the PT 
is also to be ordered alphabetically.
AET013
Incidence of TEAEs with a fatal outcome will be presented by primary 
SOC and PT.  The primary SOCs are to be ordered alphabetically.  
Within each SOC, the PT is also to be ordered alphabetically.
AET014
Prevalence of TEAEs within each consecutive 3005 Treatment Year (as 
defined in Section 6.4.9) will be summarized.  A default frequency table 
by primary SOC and PT will be presented.  The primary SOCs are to be 
ordered alphabetically.  Within each SOC, the PT is also to be ordered 
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9.11.2
Clinical Laboratory Evaluation
All laboratory tests will be presented in System International (S.I.) units only, unless 
otherwise specified.
Subject Samples:
Tables
Safety sample
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
LB
Standard Presentations
LBT001
For those variables with a PCS criterion (as defined in Table 4) the 
incidence of marked abnormalities per laboratory parameter will be 
presented.  The percentage per parameter is defined as the ratio of the 
number of subjects with at least one PCS value occurring at a post-
baseline visit and the total number of subjects in the subject sample with 
a post-baseline measurement of the specified parameter.
LBT002
Summary of quantitative special laboratory parameters for determination 
of vitamin deficiencies, for all centers/countries combined, using default 
summary statistics.  At each assessed visit, summary statistics will be 
presented as well as for the change from Baseline at each post-baseline 
visit.
LBT003
The incidence of values above and below the reference range for the 
quantitative special laboratory parameters for determination of vitamin 
deficiencies will be presented.  The percentage per parameter is defined 
as the ratio of the number of subjects with at least one value above 
(below) the reference range at a post-baseline visit and the total number 
of subjects in the subject sample with a post-baseline measurement of the 
specified parameter.
The laboratory test data will be presented in subject data listings as follows:
 


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LBL001
Hematology laboratory test data will be presented by-subject and within-
subject by sample collection date and laboratory test, including the 
relevant reference ranges.
LBL002
Chemistry laboratory test data will be presented by-subject and within-
subject by sample collection date and laboratory test, including the 
relevant reference ranges.
LBL003
Urinalysis laboratory test data will be presented by-subject and within-
subject by sample collection date and laboratory test, including the 
relevant reference ranges.
LBL004
Laboratory test data will be presented by-subject and within-subject by 
laboratory test.  PCS values will be identified and only subjects with one 
or more PCS values for the laboratory test will be presented.
9.11.3
Vital Signs
Subject Samples:
Tables
Safety sample
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
VS
Standard Presentations
VST001
Summary of quantitative vital signs assessments will be presented, for all 
centers/countries combined, using default summary statistics.  At each 
assessed visit, summary statistics will be presented as well as for the 
change from Baseline at each post-baseline visit.
VST002
For each variable with a PCS criterion (as presented in Table 5), the 
incidence of PCS values will be presented.  The percentage per parameter 
is defined as the ratio of the number of subjects with at least one PCS 
value occurring at a post baseline visit that is more extreme than their 
baseline value and the total number of subjects in the subject sample with 
a post baseline measurement of the specified parameter.
 


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In addition, all vital signs data will be presented as follows:
VSL001
A listing of PCS values together with standard demographic data will be 
presented by-subject and within-subject by PCS vital signs test criterion 
by visit.
VSL002
Vital signs data will be presented by-subject and within-subject by vital 
signs test and visit.
Study Specific Presentations
VST003
For each variable with a PCS criterion (as presented in Table 5), the 
incidence of PCS values will be presented by visit.  For a specific visit, 
the percentage per parameter is defined as the ratio of the number of 
subjects with at least one PCS value occurring at a specific post-baseline 
visit that is more extreme than their baseline value and the total number 
of subjects in the subject sample with a post baseline measurement of the 
specified parameter for the visit.
9.11.4
Electrocardiogram (ECG) Evaluations
Subject Samples:
Tables
Not applicable
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
EG
Standard Presentations
Standard ECG parameters and any abnormal findings, if applicable, will be presented in 
subject data listings as follows:
EGL001
ECG data will be presented by-subject and within-subject by visit and 
parameter and/or findings.
 


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EGL002
ECG data will be presented by-subject and within-subject by parameter.  
PCS values will be identified and only subjects with one or more PCS 
values for the parameter will be presented.
9.11.5
Other Safety Analyses
Other safety analyses will include device complications, PEG and J tube replacements and 
average duration, the sleep attack questions, Minnesota Impulsive Disorder Interview 
(MIDI), Columbia Suicide Severity Rating Scale (C-SSRS), melanoma check and 
neurological examination.  Device complications will be reported on a per-subject basis.  
This implies that even if a subject reported the same complication repeatedly 
(complications that map to the same PT or that result in the same action taken), the 
complication will be counted only once.
Subject Samples:
Tables
Safety sample and US subset of safety sample
Listings
All subjects consented
Figures
Not applicable
Subgroups:
Not applicable
Abbreviation:
DC, DI, PE, QS
Study Specific Presentations
DCT001
The incidence of device complications overall and by complication type 
will be presented, for all centers/countries combined, using default 
summary statistics.  A table will be produced for all device complications 
as well as for the subset of device complications that resulted in an AE.
DCT002
The incidence of device complications overall and for each MedDRA PT 
will be presented, for all centers/countries combined, using default 
summary statistics.  A table will be produced for all device complications 
as well as for the subset of device complications that resulted in an AE.
 


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DCT003
The incidence of device complications overall and for each MedDRA PT 
will be summarized within each 3005 Treatment Year (as defined in 
Section 6.4.9), for all centers/countries combined, using default summary 
statistics.  A table will be produced for all device complications as well 
as for the subset of device complications that resulted in an AE.
DCT004
The incidence of device complications overall and for each action taken 
will be presented, for all centers/countries combined, using default 
summary statistics.  A table will be produced for all device complications 
as well as for the subset of device complications that resulted in an AE.
DCT005
Overview of Device Complications including the number of subjects 
with:
●
At least one device complication
●
At least one device complication with action taken of tube 
replacement (either with or without surgery)
●
At least one device complication with an associated adverse event
●
At least one device complication with an associated adverse event 
and action taken of tube replacement (either with or without 
surgery).
DCT006
Overview of Device Complications (same categories as DCT005) for 
each 3005 Treatment Year (as defined in Section 6.4.9).
DIT001
A summary of PEG tube replacements will be presented, for all 
centers/countries combined, using default summary statistics.  A similar 
summary will be presented for J tube replacements.
DIT002
A summary of PEG tube and J tube replacements will be presented for 
each 3005 Treatment Year (as defined in Section 6.4.9).
DIT003
The average PEG tube and J tube duration in Study 3005 will be 
summarized with default summary statistics and with the number and
percentage of subjects with average durations in 3 month time intervals 
(≤ 91 days, 92 – 182 days, 183 to 273 days, 274 to 365 days, or 
> 365 days).
QST001
A summary of sleep attacks will be presented, for all centers/countries 
combined, using default summary statistics.
 


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QST002
A summary of the development of intense impulsive behavior as assessed 
by the Minnesota Impulsive Disorders Interview (MIDI) will be 
presented, for all centers/countries combined, using default summary 
statistics.
QST003
A summary of suicidal ideation and behavior as assessed by the 
Columbia Suicide Severity Rating Scale (C-SSRS) will be presented, for 
all centers/countries combined, using default summary statistics.
In addition, the other safety analysis data will be presented as follows:
DCL001
A listing of device complications with the standard demographic data 
will be presented by-subject.
DIL001
A listing of device information with the standard demographic data will 
be presented by-subject.
PEL001
A listing of results of melanoma checks with the standard demographic 
data will be presented by-subject and within-subject by visit.
QSL008
A listing of sleep attack responses with the standard demographic data 
will be presented by-subject and within-subject by visit.
QSL009
A listing of MIDI responses and positive/negative assessment for 
impulsive behavior with the standard demographic data will be presented 
by-subject and within-subject by visit.
QSL010
A listing of C-SSRS responses with the standard demographic data will 
be presented by-subject and within-subject by visit.
10.0
Changes to Planned Analyses
10.1
Changes to the Analysis as Laid Down in the Protocol and 
Amendments
The protocol statistical methods (Section 6.2 and Section 13.3) stated that for the analysis 
of change from baseline in efficacy measures, each subject's baseline will be their baseline 
measure in the first LCIG study in which they participated (e.g., Studies S187.3.001, 
S187.3.002 or S187.3.004).  To focus the analysis on the maintenance of efficacy during 
participation in Study 3005, each subject's baseline value for the analysis of change from 
 


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baseline in efficacy measures will be the final value in the preceding open-label study.  To 
provide context, the change in each efficacy measure from initial LCIG infusion to 3005 
endpoint will also be determined and summarized. 
Protocol Section 12.1.4 identifies the following as adverse events of special interest:
●
Risks of PEG-J insertion
●
Long-term complications of PEG-J
●
Device-associated gastrointestinal disorders during long-term therapy
For consistency with current practice throughout the LCIG development program, these 
3 categories have been combined into a single category of procedure and device 
associated events (Duodopa product specific CMQ). 
11.0
References
1.
SAS® Institute Inc., Cary, North Carolina, United States of America.
2.
International Federation of Pharmaceutical Manufacturers Associations (IFPMA).  
MedDRA – Medical Dictionary for Regulated Activities.  Reston, VA.
3.
WHO-DD.  World Health Organization Collaborating Center for International 
Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden.
4.
Hauser RA, Freidlander J, Zesiewicz TA, et al.  A home diary to assess functional 
status in patients with Parkinson disease with motor fluctuations and dyskinesia.  
Clin Neuropharmacol.  2000;23(2):75-81.
5.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the internet].  
Columbia University Medical Center.  Available from: 
http//www.cssrs.columbia.edu/.
 


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12.0
Appendices
12.1
Schedules of Assessments
12.1.1
Schedule of Assessments – Amendment 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.1.2
Schedule of Assessments – Amendment 2
*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug after 
termination.
**
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
*** On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice.
****For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to 
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
a.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
b.
Will be done as clinically indicated.
c.
For women of childbearing potential.
d.
Assessment performed once yearly.
e.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits will take place at the hospital 
pharmacy and are for the sole purpose of dispensing clinical study drug and ancillary supplies.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.1.3
Schedule of Assessments – Amendment 3
Visit
Baseline
6 Monthly
Visit
Termination
Follow-Up*
Day
Final Assessment in 
Previous Study
+/– 14 Days
--
Termination 
Visit + 7 Days
Informed consent
X
Inclusion/exclusion
X
Physical exam
Xa
X
X
Neurological Exam
Xa
X
X
Weight
Xa
X
X
Vital signs
Xa
X
X
X
12-lead ECG
Xa
Xb
X
Clinical labs
Xa
Xb
X
Folic Acid, Vitamins B6, 
B12, Methylmalonic Acid 
(MMA), and 
Homocysteine Levels
Xa
X
X
β-HCGc
Xa
X
X
Adverse events
Xa
X
X
X
Concomitant medication
Xa
X
X
X
Sleep attacks
Xa
X
X
Melanoma check
Xa
Xd
X
Determination of 
continued benefit**
X
X
MIDI 
Xa
X
X
C-SSRSf
Xa
X
X
X
Complications with 
infusion device
Xa
X
X
Inspection of stoma
Xa
X
X
X
Assessment of the need to 
replace PEG-J***
X
Xd
Dispensing of study drug
X
Every 6 
weekse
Removal of PEG****
X
*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug after 
termination.
 


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**
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
*** On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice. 
****For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to 
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
a.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
b.
Will be done as clinically indicated.
c.
For women of childbearing potential.
d.
Assessment performed once yearly.
e.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits will take place at the hospital 
pharmacy and are for the sole purpose of dispensing clinical study drug and ancillary supplies.  When scheduling 
the 6 weekly drug dispensing visits, the site should always refer back to the baseline visit.  Every attempt should be 
made to bring the subject back on the original targeted dates (± 7 days).
f.
The "Already Enrolled Subjects" C-SSRS is to be the first assessment scale administered to the subject.  At each 
subsequent assessment, the "Since Last Visit" C-SSRS scale should be administered.  If the subject has previously 
completed the "Already Enrolled Subjects" scale in Study S187.3.003, the subject should complete the "Since Last 
Visit" scale at all scheduled time points outlined in Table 2 in this study.  For subjects with a C-SSRS completed at 
their Study S187.3.003 final visit, that Study S187.3.003 final visit C-SSRS assessment will be considered baseline 
for Study S187.3.005.  For all other subjects, the first C-SSRS assessment completed in this study will serve as 
baseline.
 


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12.1.4
Schedule of Assessments – Amendment 4
Visit
Baseline
6 Monthly 
Visit
Termination/ 
Transfer to 
Commercial
Follow-Up*
Day
Final Assessment in 
Previous Study
+/– 14 Days
--
Termination 
Visit + 7 Days
Informed consent
X
Inclusion/exclusion 
X
Physical exam
Xa
X
X
Neurological Exam
Xa
X
X
Weight
Xa
X
X
Vital signs
Xa
X
X
X
12-lead ECG
Xa
Xb
X
Clinical labs
Xa
Xb
X
Folic Acid, Vitamins B6, B12, 
Methylmalonic Acid (MMA), 
and Homocysteine Levels
Xa
X
X
β-HCGc
Xa
X
X
Adverse events**
Xa-------------------------------------------------------------------------------X
Concomitant medication
Xa
X
X
X
Sleep attacks
Xa
X
X
Melanoma check
Xa
Xd
X
Determination of continued 
benefit***
X
X
MIDI 
Xa
X
X
C-SSRSf
Xa
X
X
X
Complications with infusion 
device
Xa
X
X
Inspection of stoma
Xa
X
X
X
Assessment of the need to replace 
PEG-J****
X
Xd
Dispensing of study drug
X-----Every 6 weekse-----
Daily Dosing Diaryg
X
X
Parkinson's Disease Diaryg
X
X
UPDRSh
X
X
PDQ-39h
X
X
Removal of PEG*****
X
 


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*
This visit needs to be performed only if PEG-J is removed, or if the subject does not continue to receive drug after 
termination.
**
Collection of adverse events is an ongoing and continuous process, not only occurring during site visits.
***
The decision to continue subjects on LCIG treatment will be dependent upon Principal Investigator's clinical 
judgment.
**** On a yearly basis, the LCIG system check needs to be evaluated by the study gastroenterologist; frequency of 
replacement should be in accordance with local practice. 
*****For subjects deemed inappropriate for continued treatment by the Investigator, or for subjects who elect not to
continue LCIG treatment, the PEG-J will be removed, and a follow-up clinic visit will occur 1 week later.
a.
The final assessment in the previous open-label LCIG study will serve as the baseline assessment for this item.
b.
Will be done as clinically indicated.
c.
For women of childbearing potential.
d.
Assessment performed once yearly.
e.
Clinical supply visits should take place every 6 weeks ± 7 days.  These visits may take place at the hospital 
pharmacy and are for the purpose of dispensing clinical study drug and ancillary supplies.  Other assessments may 
be completed during these visits if required.  When scheduling the 6 weekly drug dispensing visits, the site should 
always refer back to the baseline visit.  Every attempt should be made to pick up drug on the original targeted dates 
(± 7 days).
f.
The "Already Enrolled Subjects" C-SSRS is to be the first assessment scale administered to the subject.  At each 
subsequent assessment, the "Since Last Visit" C-SSRS scale should be administered.  If the subject has previously 
completed the "Already Enrolled Subjects" scale in Study S187.3.003, the subject should complete the "Since Last 
Visit" scale at all scheduled time points in this study.  For subjects with a C-SSRS completed at their 
Study S187.3.003 final visit, that Study S187.3.003 final visit C-SSRS assessment will be considered baseline for 
the Study S187.3.005.  For all other subjects, the first C-SSRS assessment completed in this study will serve as 
baseline.
g.
The Daily Dosing Diary and the Parkinson's Disease Diary will be completed by subjects or their caregivers for the 
3 consecutive days prior to each clinic visit at US sites only.
h.
The UPDRS and the PDQ-39 will be completed at US sites only.
 


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12.2
List of Tables
SAP Table Code
Table Number
Table Title
DST001
14.1__1.1.1.1
Subject Disposition ALL SUBJECTS CONSENTED
DST003
14.1__1.1.1.2
Number and Percent of Premature Discontinuations by 3005 
Treatment Year   SAFETY SAMPLE
DST002
14.1__1.1.2
Analysis Samples ALL SUBJECTS CONSENTED
DVT001
14.1__1.1.3
Major Protocol Deviations SAFETY SAMPLE
DMT001
14.1__1.2.1
Demographics SAFETY SAMPLE
SCT001
14.1__1.2.2
Baseline Subject Characteristics SAFETY SAMPLE
SCT002
14.1__1.2.3
Study Specific Subject Characteristics SAFETY SAMPLE
MHT001
14.1__1.3
Medical History SAFETY SAMPLE
CMT002
14.1__1.4.1
Continuing Anti-Parkinsonian Medication Use on the First Day 
of 3005 SAFETY SAMPLE
CMT002
14.1__1.4.2
Concomitant Anti-Parkinsonian Medication Use by 3005 
Treatment Year SAFETY SAMPLE
CMT001
14.1__1.4.3
Concomitant Medications SAFETY SAMPLE
CML001
14.1__1.4.4
Listing of Concomitant Medication: General Findings SAFETY 
SAMPLE – NARROW POLYNEUROPATHY SUBSET 
DST001
14.1__2.1
Subject Disposition EFFICACY SAMPLE – US SUBSET
DMT001
14.1__2.2.1
Demographics EFFICACY SAMPLE – US SUBSET
SCT001
14.1__2.2.2
Baseline Subject Characteristics EFFICACY SAMPLE – US 
SUBSET
SCT002
14.1__2.2.3
Study Specific Subject Characteristics EFFICACY SAMPLE –
US SUBSET
CMT002
14.1__2.3.1
Continuing Anti-Parkinsonian Medication Use on the First Day 
of 3005 EFFICACY SAMPLE – US SUBSET
CMT002
14.1__2.3.2
Concomitant Anti-Parkinsonian Medication Use by 3005 
Treatment Year EFFICACY SAMPLE – US SUBSET
QST001
14.2__1.1.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary EFFICACY SAMPLE
QST001
14.2__1.1.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE
QST001
14.2__1.1.3
Change in Average Daily "On" Time With Troublesome
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE
 


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SAP Table Code
Table Number
Table Title
QST001
14.2__1.1.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE
QST001
14.2__1.1.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary EFFICACY 
SAMPLE
QST003
14.2__1.2
Clinical Global Impression – Improvement (CGI-I) at Endpoint 
EFFICACY SAMPLE
QST001
14.2__1.3.1
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Summary Index EFFICACY SAMPLE
QST001
14.2__1.3.2
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Mobility Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.3
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Activities of Daily Living Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.4
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Emotional Well-Being Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.5
Change in Parkinson's Disease Questionnaire (PDQ-39) Stigma 
Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.6
Change in Parkinson's Disease Questionnaire (PDQ-39) Social 
Support Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.7
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Cognition Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.8
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Communication Domain Score EFFICACY SAMPLE
QST001
14.2__1.3.9
Change in Parkinson's Disease Questionnaire (PDQ-39) Bodily 
Discomfort Domain Score EFFICACY SAMPLE
QST001
14.2__2.1.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.1.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.1.3
Change in Average Daily "On" Time With Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.1.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary 
EFFICACY SAMPLE – US SUBSET
 


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SAP Table Code
Table Number
Table Title
QST001
14.2__2.1.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary EFFICACY 
SAMPLE – US SUBSET
QST001
14.2__2.2.1
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Total Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.2.2
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Part I Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.2.3
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Part II Score  EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.2.4
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Part III Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.2.5
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Part IV Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.2.6
Change in Unified Parkinson's Disease rating Scale (UPDRS) 
Part IV Questions 32, 33 and 34 EFFICACY SAMPLE – US 
SUBSET
QST001
14.2__2.3.1
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Summary Index  EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.3.2
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Mobility Domain Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.3.3
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Activities of Daily Living Domain Score EFFICACY SAMPLE 
– US SUBSET
QST001
14.2__2.3.4
Change in Parkinson's Disease Questionnaire (PDQ-39)  
Emotional Well-Being Domain Score EFFICACY SAMPLE –
US SUBSET
QST001
14.2__2.3.5
Change in Parkinson's Disease Questionnaire (PDQ-39) Stigma 
Domain Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.3.6
Change in Parkinson's Disease Questionnaire (PDQ-39) Social 
Support Domain Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.3.7
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Cognition Domain Score EFFICACY SAMPLE – US SUBSET
QST001
14.2__2.3.8
Change in Parkinson's Disease Questionnaire (PDQ-39) 
Communication Domain Score EFFICACY SAMPLE – US 
SUBSET
QST001
14.2__2.3.9
Change in Parkinson's Disease Questionnaire (PDQ-39)  Bodily 
Discomfort Domain Score  EFFICACY SAMPLE – US 
SUBSET
 


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SAP Table Code
Table Number
Table Title
QST002
14.2__2.4.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary in Subgroups Determined by the Study 
of First LCIG Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.4.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by the Study of First LCIG Infusion 
EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.4.3
Change in Average Daily "On" Time With Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by the Study of First LCIG Infusion 
EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.4.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by the Study of First LCIG Infusion 
EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.4.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary in Subgroups 
Determined by the Study of First LCIG Infusion EFFICACY 
SAMPLE – US SUBSET
QST002
14.2__2.5.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary in Subgroups Determined by 
Troublesome Dyskinesia at Initial LCIG Infusion EFFICACY 
SAMPLE – US SUBSET
QST002
14.2__2.5.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Troublesome Dyskinesia at Initial 
LCIG Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.5.3
Change in Average Daily "On" Time With Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Troublesome Dyskinesia at Initial 
LCIG Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.5.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Troublesome Dyskinesia at Initial 
LCIG Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.5.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary in Subgroups 
Determined by Troublesome Dyskinesia at Initial LCIG 
Infusion EFFICACY SAMPLE – US SUBSET
 


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SAP Table Code
Table Number
Table Title
QST002
14.2__2.6.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary in Subgroups Determined by Levodopa 
Monotherapy in Study S187.3.005 EFFICACY SAMPLE – US 
SUBSET
QST002
14.2__2.6.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Levodopa Monotherapy in Study 
S187.3.005 EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.6.3
Change in Average Daily "On" Time With Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary  
in Subgroups Determined by Levodopa Monotherapy in Study 
S187.3.005 EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.6.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Levodopa Monotherapy in Study 
S187.3.005 EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.6.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary in Subgroups 
Determined by Levodopa Monotherapy in Study S187.3.005 
EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.7.1
Change in Average Daily "Off" Time Based on the Parkinson's 
Disease Symptom Diary in Subgroups Determined by Levodopa 
Dose at Initial LCIG Infusion EFFICACY SAMPLE – US 
SUBSET
QST002
14.2__2.7.2
Change in Average Daily "On" Time Without Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary in 
Subgroups Determined by Levodopa Dose at Initial LCIG 
Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.7.3
Change in Average Daily "On" Time With Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary  
in Subgroups Determined by Levodopa Dose at Initial LCIG 
Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.7.4
Change in Average Daily "On" Time With Non Troublesome 
Dyskinesia Based on the Parkinson's Disease Symptom Diary  
in Subgroups Determined by Levodopa Dose at Initial LCIG 
Infusion EFFICACY SAMPLE – US SUBSET
QST002
14.2__2.7.5
Change in Average Daily "On" Time Without Dyskinesia Based 
on the Parkinson's Disease Symptom Diary in Subgroups 
Determined by Levodopa Dose at Initial LCIG Infusion 
EFFICACY SAMPLE – US SUBSET
 


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SAP Table Code
Table Number
Table Title
EXT001
14.3__1.1.1.1
Duration of 3005 Levodopa-Carbidopa Intestinal Gel (LCIG) 
Exposure SAFETY SAMPLE
EXT001
14.3__1.1.1.2
Duration of 3005 PEG-J Exposure SAFETY SAMPLE
EXT001
14.3__1.1.2.1
Overall Duration of Levodopa-Carbidopa Intestinal Gel (LCIG) 
Exposure SAFETY SAMPLE
EXT001
14.3__1.1.2.2
Overall Duration of PEG-J Exposure SAFETY SAMPLE
EXT001
14.3__1.1.3.1
Duration of 3005 Levodopa-Carbidopa Intestinal Gel (LCIG) 
Exposure SAFETY SAMPLE – US SUBSET
EXT001
14.3__1.1.3.2
Duration of 3005 PEG-J Exposure SAFETY SAMPLE – US 
SUBSET
EXT001
14.3__1.1.4.1
Overall Duration of Levodopa-Carbidopa Intestinal Gel (LCIG) 
Exposure SAFETY SAMPLE – US SUBSET
EXT001
14.3__1.1.4.2
Overall Duration of PEG-J Exposure SAFETY SAMPLE – US 
SUBSET
EXT002
14.3__1.1.5
Prescribed Dosing Level at the Conclusion of the Previous 
S187.3.004 Study SAFETY SAMPLE
EXT003
14.3__1.1.6
Dose of Levodopa-Carbidopa Intestinal Gel Administered 
SAFETY SAMPLE – US SUBSET
EXT004
14.3__1.1.7
Dose of Levodopa-Carbidopa Intestinal Gel Administered in 
Subgroups Determined by the Study of First LCIG Infusion 
SAFETY SAMPLE – US SUBSET
AET001
14.3__1.2.1.1
Summary of Adverse Events SAFETY SAMPLE
AET002
14.3__1.2.1.2
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events SAFETY SAMPLE
AET003
14.3__1.2.1.3
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events by Descending Frequency SAFETY SAMPLE
AET011
14.3__1.2.1.4
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events by 3005 Treatment Year SAFETY SAMPLE
AET007
14.3__1.2.1.5
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events by Strongest Relationship SAFETY SAMPLE
AET008
14.3__1.2.1.6
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events that are at Least Possibly Related to Treatment 
SAFETY SAMPLE
AET010
14.3__1.2.1.7
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Linked to Device Complications by the Device 
Complications CRF SAFETY SAMPLE
 


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SAP Table Code
Table Number
Table Title
AET009
14.3__1.2.1.8
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events by Maximum Severity (Investigator's 
Judgment) SAFETY SAMPLE
AET014
14.3__1.2.1.9
Prevalence of Treatment-Emergent Adverse Events by 3005 
Treatment Year   SAFETY SAMPLE
AET013
14.3__1.2.2.1
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events with Fatal Outcome SAFETY SAMPLE
AET004
14.3__1.2.2.2
Number and Percent of Subjects with Treatment-Emergent 
Serious Adverse Events SAFETY SAMPLE
AET005
14.3__1.2.2.3
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Termination SAFETY 
SAMPLE
AET006
14.3__1.2.2.4
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Procedure and 
Device SAFETY SAMPLE
AET011
14.3__1.2.2.5
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Procedure and 
Device by 3005 Treatment Year   SAFETY SAMPLE
AET014
14.3__1.2.2.6
Prevalence of Treatment-Emergent Adverse Events of Special 
Interest Related to Procedure and Device by 3005 Treatment 
Year   SAFETY SAMPLE
AET006
14.3__1.2.2.7
Number and Percent of Subjects with Treatment-Emergent 
Serious Adverse Events of Special Interest Related to Procedure 
and Device SAFETY SAMPLE
AET006
14.3__1.2.2.8
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Procedure and 
Device Leading to Study Termination   SAFETY SAMPLE
AET006
14.3__1.2.2.9
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Not Related to Procedure and Device SAFETY 
SAMPLE 
AET011
14.3__1.2.2.10
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Not Related to Procedure and Device by 3005 
Treatment Year SAFETY SAMPLE
AET014
14.3__1.2.2.11
Prevalence of Treatment-Emergent Adverse Events Not Related 
to Procedure and Device by 3005 Treatment Year   SAFETY 
SAMPLE
AET006
14.3__1.2.2.12
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Polyneuropathy 
and Associated Signs and Symptoms (Broad Search)  SAFETY 
SAMPLE 
 


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SAP Table Code
Table Number
Table Title
AET006
14.3__1.2.2.13
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Polyneuropathy 
and Associated Signs and Symptoms (Narrow Search)  
SAFETY SAMPLE
AET006
14.3__1.2.2.14
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Weight Loss 
SAFETY SAMPLE 
AET006
14.3__1.2.2.15
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Cardiovascular 
Fatalities SAFETY SAMPLE
AET006
14.3__1.2.2.16
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Aspiration 
SAFETY SAMPLE
AET012
14.3__1.2.3.1
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Subgroup:  Gender SAFETY SAMPLE
AET012
14.3__1.2.3.2
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Subgroup:  Age Category SAFETY SAMPLE
AET012
14.3__1.2.3.3
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Subgroup:  Duration of Parkinson's Disease 
SAFETY SAMPLE
AET012
14.3__1.2.3.4
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Subgroup:  Country SAFETY SAMPLE
AET001
14.3__1.2.4.1
Summary of Adverse Events SAFETY SAMPLE – US 
SUBSET
AET002
14.3__1.2.4.2
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events SAFETY SAMPLE – US SUBSET
AET013
14.3__1.2.4.3
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events with Fatal Outcome SAFETY SAMPLE – US 
SUBSET
AET004
14.3__1.2.4.4
Number and Percent of Subjects with Treatment-Emergent 
Serious Adverse Events SAFETY SAMPLE – US SUBSET
AET005
14.3__1.2.4.5
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Leading to Study Termination SAFETY 
SAMPLE – US SUBSET
AET006
14.3__1.2.4.6
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Procedure and 
Device SAFETY SAMPLE – US SUBSET
AET006
14.3__1.2.4.7
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events Not Related to Procedure and Device SAFETY 
SAMPLE – US SUBSET
 


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SAP Table Code
Table Number
Table Title
AET006
14.3__1.2.4.8
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Polyneuropathy 
and Associated Signs and Symptoms SAFETY SAMPLE – US 
SUBSET
AET006
14.3__1.2.4.9
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Weight Loss 
SAFETY SAMPLE – US SUBSET
AET006
14.3__1.2.4.10
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Cardiovascular 
Fatalities SAFETY SAMPLE – US SUBSET
AET006
14.3__1.2.4.11
Number and Percent of Subjects with Treatment-Emergent 
Adverse Events of Special Interest Related to Aspiration 
SAFETY SAMPLE – US SUBSET
AEL003
14.3__2.1
Listing of Subject Deaths SAFETY SAMPLE
AEL004
14.3__2.2
Listing of Serious Adverse Events SAFETY SAMPLE
AEL005
14.3__2.3
Listing of Adverse Events Leading to Study Termination 
SAFETY SAMPLE
AEL006
14.3__2.4
Listing of Adverse Events of Special Interest Related to 
Procedure and Device SAFETY SAMPLE
AEL006
14.3__2.5
Listing of Adverse Events of Special Interest Related to 
Polyneuropathy SAFETY SAMPLE
AEL006
14.3__2.6
Listing of Adverse Events of Special Interest Related to Weight 
Loss SAFETY SAMPLE
AEL006
14.3__2.7
Listing of Adverse Events of Special Interest Related to 
Cardiovascular Fatalities SAFETY SAMPLE
AEL006
14.3__2.8
Listing of Adverse Events of Special Interest Related to 
Aspiration SAFETY SAMPLE
LBT001
14.3__4.1.1
Number and Percentage of Subjects with Potentially Clinically 
Significant Hematology Laboratory Parameters SAFETY 
SAMPLE
LBL002
14.3__4.1.2
Listing of Potentially Clinically Significant Hematology 
Laboratory Parameters SAFETY SAMPLE
LBT001
14.3__4.2.1
Number and Percentage of Subjects with Potentially Clinically 
Significant Chemistry Laboratory Parameters SAFETY 
SAMPLE
LBL002
14.3__4.2.2
Listing of Potentially Clinically Significant Chemistry 
Laboratory Parameters SAFETY SAMPLE
LBT002
14.3__4.3.1
Summary of Quantitative Special Laboratory Parameters for 
Determination of Vitamin Deficiency SAFETY SAMPLE
 


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SAP Table Code
Table Number
Table Title
LBT003
14.3__4.3.2
Number and Percent of Subjects with Quantitative Special 
Laboratory Parameters for Determination of Vitamin Deficiency 
Outside of the Reference Range   SAFETY SAMPLE
LBT002
14.3__4.4.1
Summary of Quantitative Special Laboratory Parameters for 
Determination of Vitamin Deficiency SAFETY SAMPLE –
NARROW POLYNEUROPATHY SUBSET
LBT003
14.3__4.4.2
Number and Percent of Subjects with Quantitative Special 
Laboratory Parameters for Determination of Vitamin Deficiency 
Outside of the Reference Range   SAFETY SAMPLE –
NARROW POLYNEUROPATHY SUBSET
LBL002
14.3__4.4.3
Listing of Chemistry Determinations   SAFETY SAMPLE –
NARROW POLYNEUROPATHY SUBSET
VST001
14.3__5.1.1
Summary of Supine Systolic Blood Pressure (mmHg) SAFETY 
SAMPLE
VST001
14.3__5.1.2
Summary of Standing Systolic Blood Pressure (mmHg) 
SAFETY SAMPLE
VST001
14.3__5.1.3
Summary of Orthostatic Systolic Blood Pressure (mmHg) 
SAFETY SAMPLE
VST001
14.3__5.1.4
Summary of Supine Diastolic Blood Pressure (mmHg) 
SAFETY SAMPLE
VST001
14.3__5.1.5
Summary of Standing Diastolic Blood Pressure (mmHg) 
SAFETY SAMPLE
VST001
14.3__5.1.6
Summary of Orthostatic Diastolic Blood Pressure (mmHg) 
SAFETY SAMPLE
VST001
14.3__5.1.7
Summary of Supine Pulse (bpm) SAFETY SAMPLE
VST001
14.3__5.1.8
Summary of Standing Pulse (bpm) SAFETY SAMPLE
VST001
14.3__5.1.9
Summary of Orthostatic Pulse (bpm) SAFETY SAMPLE
VST001
14.3__5.1.10
Summary of Temperature (Celsius) SAFETY SAMPLE
VST001
14.3__5.1.11
Summary of Weight (kg) SAFETY SAMPLE
VST002
14.3__5.2.1
Number and Percent of Subjects with Potentially Clinically 
Significant Vital Sign Values SAFETY SAMPLE
VST003
14.3__5.2.2
Number and Percent of Subjects with Potentially Clinically 
Significant Vital Sign Values by Visit  SAFETY SAMPLE
VSL001
14.3__5.2.3
Listing of Potentially Clinically Significant Vital Sign 
Parameters SAFETY SAMPLE
DCT005
14.3__6.1.1
Overview of Device Complications   SAFETY SAMPLE
DCT006
14.3__6.1.2
Overview of Device Complications by 3005 Treatment Year   
SAFETY SAMPLE
 


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SAP Table Code
Table Number
Table Title
DCT001
14.3__6.1.3
Number and Percent of Subjects with Device Complications by 
Type SAFETY SAMPLE 
DCT002
14.3__6.1.4
Number and Percent of Subjects with Device Complications by 
MedDRA Preferred Term SAFETY SAMPLE  
DCT003
14.3__6.1.5
Number and Percent of Subjects with Device Complications by 
MedDRA Preferred Term and 3005 Treatment Year SAFETY 
SAMPLE  
DCT004
14.3__6.1.6
Number and Percent of Subjects with Device Complications by 
Action Taken SAFETY SAMPLE
DCT002
14.3__6.1.7
Number and Percent of Subjects with Device Complications 
with Action Taken of Tube Replacement by MedDRA Preferred 
Term SAFETY SAMPLE  
DCT001
14.3__6.2.1
Number and Percent of Subjects with Device Complication 
Related to Adverse Events by Type SAFETY SAMPLE
DCT002
14.3__6.2.2
Number and Percent of Subjects with Device Complication 
Related to Adverse Events by MedDRA Preferred Term 
SAFETY SAMPLE 
DCT003
14.3__6.2.3
Number and Percent of Subjects with Device Complication 
Related to Adverse Events by MedDRA Preferred Term and 
3005 Treatment Year SAFETY SAMPLE 
DCT004
14.3__6.2.4
Number and Percent of Subjects with Device Complication 
Related to Adverse Events by Action Taken SAFETY SAMPLE
DCT002
14.3__6.3.1
Number and Percent of Subjects with Device Complication by 
MedDRA Preferred Term SAFETY SAMPLE – US SUBSET
DCT002
14.3__6.3.2
Number and Percent of Subjects with Device Complication 
Related to Adverse Events by MedDRA Preferred Term 
SAFETY SAMPLE – US SUBSET
DIT001
14.3__6.4.1.1
Number of PEG Tube Replacements SAFETY SAMPLE
DIT001
14.3__6.4.1.2
Number of J Tube Replacements SAFETY SAMPLE
DIT002
14.3__6.4.2
Number of PEG Tube and J Tube Replacements by 3005 
Treatment Year   SAFETY SAMPLE
DIT001
14.3__6.4.3.1
Number of PEG Tube Replacements before 3005 Study Start   
SAFETY SAMPLE
DIT001
14.3__6.4.3.2
Number of J Tube Replacements before 3005 Study Start   
SAFETY SAMPLE
DIT003
14.3__6.4.4.1
Average PEG Tube Duration in Study 3005  SAFETY 
SAMPLE
DIT003
14.3__6.4.4.2
Average J Tube Duration in Study 3005  SAFETY SAMPLE
 


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SAP Table Code
Table Number
Table Title
QST001
14.3__7.1
Summary of Sleep Attacks SAFETY SAMPLE
QST002
14.3__7.2
Summary of Minnesota Impulsive Disorder Interview (MIDI) 
SAFETY SAMPLE
QST003
14.3__7.3
Summary of Columbia Suicide Severity Rating Scale (C-SSRS) 
SAFETY SAMPLE
12.3
List of Listings
SAP Listing Code
Listing Number
Listing Title
DSL001
16.2__1.1
Listing of Subjects Who Prematurely Terminated the Study 
Prior to Receiving 3005 LCIG Infusion ALL SUBJECTS 
CONSENTED
DSL002
16.2__1.2
Listing of Subjects Who Prematurely Terminated the Study 
After Receiving 3005 LCIG Infusion ALL SUBJECTS 
CONSENTED
DSL003
16.2__1.3
Listing of Subject Samples ALL SUBJECTS CONSENTED
DVL001
16.2__2.1
Listing of Subjects with Major Protocol Deviations ALL 
SUBJECTS CONSENTED
IEL001
16.2__3.1
Listing of Subjects with Deviations from Inclusion or 
Exclusion Criteria ALL SUBJECTS CONSENTED
DML001
16.2__4.1
Listing of Demographics ALL SUBJECTS CONSENTED
SCL001
16.2__4.2
Listing of Baseline Vital Signs ALL SUBJECTS 
CONSENTED
SCL002
16.2__4.3
Listing of Parkinson's Disease Duration and Diagnosis Data 
ALL SUBJECTS CONSENTED
MHL001
16.2__4.4
Listing of Medical History:  General Findings ALL 
SUBJECTS CONSENTED
MHL002
16.2__4.5
Listing of Medical History:  MedDRA Coding ALL 
SUBJECTS CONSENTED
SCL004
16.2__4.6
Listing of PD Medication Use Prior to Study Start:  General 
Findings ALL SUBJECTS CONSENTED
SCL005
16.2__4.7
Listing of PD Medication Use Prior to Study Start:  WHO-
DD Coding ALL SUBJECTS CONSENTED
CML001
16.2__4.8
Listing of Concomitant Medication:  General Findings ALL 
SUBJECTS CONSENTED
CML002
16.2__4.9
Listing of Concomitant Medication:  WHO-DD Coding  
ALL SUBJECTS CONSENTED
 


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SAP Listing Code
Listing Number
Listing Title
DAL001
16.2__5.1
Listing of Cassettes Dispensed, Used and Returned ALL 
SUBJECTS CONSENTED
EXL001
16.2__5.2
Listing of Study Drug Exposure and Treatment Duration 
ALL SUBJECTS CONSENTED
EXL002
16.2__5.3
Listing of LCIG Titration in Study 3005 ALL SUBJECTS 
CONSENTED
QSL001
16.2__6.1
Listing of Parkinson's Disease Symptom Diary ALL 
SUBJECTS CONSENTED
QSL002
16.2__6.2
Listing of Clinical Global Impression – Improvement (CGI-I) 
ALL SUBJECTS CONSENTED
QSL003
16.2__6.3
Listing of Parkinson's Disease Quality of Life Questionnaire 
ALL SUBJECTS CONSENTED
QSL004
16.2__6.4
Listing of Unified Parkinson's Disease Rating Scale 
(UPDRS) ALL SUBJECTS CONSENTED
AEL001
16.2__7.1
Listing of Adverse Events:  General Findings ALL 
SUBJECTS CONSENTED
AEL002
16.2__7.2
Listing of Adverse Events:  MedDRA Coding ALL 
SUBJECTS CONSENTED
LBL001
16.2__8.1.1
Listing of Hematology Determinations ALL SUBJECTS 
CONSENTED
LBL002
16.2__8.1.2
Listing of Chemistry Determinations ALL SUBJECTS 
CONSENTED
LBL003
16.2__8.1.3
Listing of Urinalysis Determinations ALL SUBJECTS 
CONSENTED
LBL004
16.2__8.1.4
Listing of Abnormal Laboratory Results ALL SUBJECTS 
CONSENTED
EGL001
16.2__8.2.1
Listing of ECG Assessments by Investigators ALL 
SUBJECTS CONSENTED
EGL002
16.2__8.2.2
Listing of ECG Assessments by ECG Central Reader ALL 
SUBJECTS CONSENTED
VSL002
16.2__8.3
Listing of Vital Signs ALL SUBJECTS CONSENTED 
QSL008
16.2__8.4
Listing of Sleep Attack Data ALL SUBJECTS 
CONSENTED
QSL009
16.2__8.5
Listing of Minnesota Impulsive Disorders Interview ALL 
SUBJECTS CONSENTED
PEL001
16.2__8.6
Listing of Results of Melanoma Checks ALL SUBJECTS 
CONSENTED
 


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SAP Listing Code
Listing Number
Listing Title
DCL001
16.2__8.7
Listing of Device Complications ALL SUBJECTS 
CONSENTED
DIL001
16.2__8.8
Listing of Pump and Tube Information ALL SUBJECTS 
CONSENTED
SCL001
16.2__8.9
Listing of LCIG System Checks ALL SUBJECTS 
CONSENTED
INL001
16.2__8.10
Listing of Stoma Site Inspections ALL SUBJECTS 
CONSENTED
IML001
16.2__8.11
Listing of Radiological Tube Placement Checks ALL 
SUBJECTS CONSENTED
HUL001
16.2__8.12
Listing of Hospitalizations  ALL SUBJECTS CONSENTED
CBL001
16.2__8.13
Listing of Determination of Continued LCIG Benefit ALL 
SUBJECTS CONSENTED
NEL001
16.2__8.14
Listing of Neurological Examination Results ALL 
SUBJECTS CONSENTED
QSL010
16.2__8.15
Listing of Columbia Suicide Severity Rating Scale (C-SSRS) 
Responses ALL SUBJECTS CONSENTED 
12.4
List of MedDRA Preferred Terms for Adverse Events of 
Special Interest
1.
Procedure and device associated events (Duodopa Product Specific 
CMQ 80000111).
Code
Preferred Term
10000059
Abdominal discomfort
10060923
Abdominal hernia obstructive
10060924
Abdominal injury
10000081
Abdominal pain
10000084
Abdominal pain lower
10000087
Abdominal pain upper
10000099
Abdominal wall abscess
10066337
Abdominal wound dehiscence
10000647
Acute abdomen
10069773
Administration related reaction
 


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Code
Preferred Term
10049555
Anal haemorrhage
10002243
Anastomotic ulcer
10002244
Anastomotic ulcer haemorrhage
10002248
Anastomotic ulcer perforation
10003445
Ascites
10004542
Bezoar
10067442
Bloody peritoneal effluent
10069801
Cardiac complication associated with device
10053183
Catheter site cellulitis
10068607
Catheter site erosion
10056520
Catheter site infection
10070776
Chemical burn of gastrointestinal tract
10050399
Chronic gastrointestinal bleeding
10009900
Colitis ulcerative
10052931
Colon fistula repair
10009995
Colonic fistula
10010000
Colonic obstruction
10057078
Colonic pseudo-obstruction
10010004
Colonic stenosis
10064538
Complication of device insertion
10010151
Complication of device removal
10057798
Computerised tomogram abdomen abnormal
10012575
Device breakage
10069872
Device chemical property issue
10069873
Device colour issue
10069869
Device component issue
10065066
Device connection issue
10069870
Device damage
10070691
Device deployment issue
10070692
Device deposit issue
10069845
Device-device incompatibility
10069853
Device difficult to use
10064684
Device dislocation
 


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Code
Preferred Term
10012578
Device expulsion
10070614
Device extension damage
10012579
Device extrusion
10056871
Device failure
10059875
Device ineffective
10070617
Device infusion issue
10012586
Device interaction
10068444
Device intolerance
10070618
Device inversion
10069868
Device issue
10070305
Device kink
10012587
Device leakage
10063829
Device malfunction
10069871
Device material issue
10069879
Device material opacification
10067161
Device misuse
10064685
Device occlusion
10069880
Device physical property issue
10064687
Device related infection
10069802
Device related sepsis
10063371
Device therapy
10068139
Device toxicity
10013474
Distal ileal obstruction syndrome
10056361
Distal intestinal obstruction syndrome
10070470
Drug administered in wrong device
10056586
Drug delivery device implantation
10056590
Drug delivery device removal
10013828
Duodenal fistula
10013830
Duodenal obstruction
10013832
Duodenal perforation
10050094
Duodenal stenosis
10013836
Duodenal ulcer
10013839
Duodenal ulcer haemorrhage
 


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Code
Preferred Term
10013855
Duodenal ulcer, obstructive
10013849
Duodenal ulcer perforation
10013850
Duodenal ulcer perforation, obstructive
10069807
Duodenal ulcer repair
10013864
Duodenitis
10013865
Duodenitis haemorrhagic
10064826
Duodenoenterostomy
10014896
Enterocolitis haemorrhagic
10056991
Enterocolonic fistula
10051425
Enterocutaneous fistula
10057005
Enterostomy
10057074
Enterostomy closure
10062570
Enterovesical fistula
10062532
Erosive duodenitis
10063655
Erosive oesophagitis
10071039
Excessive dietary fibre intake
10063560
Excessive granulation tissue
10068515
Exposure to contaminated device
10056661
Feeding tube complication
10067143
Fistula discharge
10071275
Functional gastrointestinal disorder
10061138
Fungal peritonitis
10065713
Gastric fistula
10071259
Gastric fistula repair
10017788
Gastric haemorrhage
10058035
Gastric ileus
10070994
Gastric mucosa erythema
10017807
Gastric mucosal hypertrophy
10061164
Gastric mucosal lesion
10067855
Gastric occult blood positive
10017815
Gastric perforation
10061970
Gastric stenosis
10017822
Gastric ulcer
 


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Code
Preferred Term
10017826
Gastric ulcer haemorrhage
10017829
Gastric ulcer haemorrhage, obstructive
10051348
Gastric ulcer helicobacter
10017835
Gastric ulcer perforation
10017836
Gastric ulcer perforation, obstructive
10017840
Gastric ulcer, obstructive
10057348
Gastric ulcer surgery
10057572
Gastric varices haemorrhage
10017860
Gastritis atrophic
10017865
Gastritis erosive
10017866
Gastritis haemorrhagic
10053768
Gastroduodenal haemorrhage
10017886
Gastroduodenal ulcer
10048712
Gastroduodenitis haemorrhagic
10017873
Gastro-enterostomy
10017928
Gastrointestinal angiodysplasia
10017929
Gastrointestinal angiodysplasia haemorrhagic
10017944
Gastrointestinal disorder
10061171
Gastrointestinal disorder postoperative
10053074
Gastrointestinal disorder therapy
10060709
Gastrointestinal erosion
10017877
Gastrointestinal fistula
10071258
Gastrointestinal fistula repair
10017955
Gastrointestinal haemorrhage
10052105
Gastrointestinal hypomotility
10061172
Gastrointestinal injury
10059028
Gastrointestinal ischaemia
10061173
Gastrointestinal motility disorder
10056995
Gastrointestinal mucosal disorder
10017980
Gastrointestinal mucosal necrosis
10017982
Gastrointestinal necrosis
10061974
Gastrointestinal obstruction
10018001
Gastrointestinal perforation
 


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Code
Preferred Term
10018007
Gastrointestinal stenosis
10065718
Gastrointestinal stoma complication
10065712
Gastrointestinal stoma necrosis
10070840
Gastrointestinal tract irritation
10053050
Gastrointestinal tube insertion
10061459
Gastrointestinal ulcer
10056743
Gastrointestinal ulcer haemorrhage
10057161
Gastrointestinal ulcer management
10061975
Gastrointestinal ulcer perforation
10017882
Gastro-jejunostomy
10018044
Gastroparesis postoperative
10067091
Gastropleural fistula
10068792
Gastrosplenic fistula
10050056
Gastrostomy failure
10059766
Haemorrhagic ascites
10067786
Haemorrhagic erosive gastritis
10061213
Iatrogenic injury
10065728
Ileal fistula
10021305
Ileal perforation
10021307
Ileal stenosis
10021309
Ileal ulcer
10021310
Ileal ulcer perforation
10021312
Ileitis
10021319
Ileojejunal bypass
10021328
Ileus
10021333
Ileus paralytic
10021335
Ileus spastic
10063860
Implant site induration
10063869
Implant site ulcer
10049660
Incision site abscess
10067990
Incision site blister
10064109
Incision site cellulitis
10059048
Incision site complication
 


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Code
Preferred Term
10065615
Incision site erythema
10059241
Incision site haematoma
10051100
Incision site haemorrhage
10065616
Incision site infection
10065614
Incision site oedema
10058043
Incision site pain
10059386
Incision site pruritus
10068945
Incorrect dose administered by device
10021784
Infected skin ulcer
10071647
Infectious peritonitis
10065464
Infusion site haemorrhage
10054995
Infusion site ulcer
10069803
Injury associated with device
10070773
Intentional medical device removal by patient
10068575
Intestinal anastomosis complication
10022642
Intestinal dilatation
10022647
Intestinal fistula
10051095
Intestinal fistula infection
10052991
Intestinal fistula repair
10069829
Intestinal haematoma
10059175
Intestinal haemorrhage
10022657
Intestinal infarction
10022680
Intestinal ischaemia
10022687
Intestinal obstruction
10022694
Intestinal perforation
10071197
Intestinal polyp haemorrhage
10022699
Intestinal stenosis
10022714
Intestinal ulcer
10061248
Intestinal ulcer perforation
10061249
Intra-abdominal haemorrhage
10066127
Ischaemic pancreatitis
10065719
Jejunal fistula
10023172
Jejunal gangrene
 


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Code
Preferred Term
10062027
Jejunal operation
10023174
Jejunal perforation
10023176
Jejunal stenosis
10023177
Jejunal ulcer
10023178
Jejunal ulcer perforation
10023180
Jejunostomy
10023694
Laparoscopy abnormal
10052534
Large intestinal haemorrhage
10062062
Large intestinal obstruction
10023794
Large intestinal obstruction reduction
10023799
Large intestinal ulcer
10061262
Large intestinal ulcer haemorrhage
10023804
Large intestine perforation
10066768
Localized intraabdominal fluid collection
10050953
Lower gastrointestinal haemorrhage
10026712
Mallory-Weiss syndrome
10051399
Mechanical ileus
10057075
Meconium plug syndrome
10059108
Medical device change
10057281
Medical device complication
10053683
Medical device discomfort
10070765
Medical device entrapment
10049812
Medical device implantation
10059057
Medical device pain
10052971
Medical device removal
10062680
Medical device site reaction
10069699
Mesenteric traction syndrome
10028084
Mucocutaneous ulceration
10061297
Mucosal erosion
10061298
Mucosal haemorrhage
10067993
Mucosal necrosis
10028124
Mucosal ulceration
10061876
Obstruction
 


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Code
Preferred Term
10029957
Obstruction gastric
10052400
Oedematous pancreatitis
10030172
Oesophageal haemorrhage
10070818
Oesophageal irritation
10030178
Oesophageal obstruction
10030181
Oesophageal perforation
10030194
Oesophageal stenosis
10030201
Oesophageal ulcer
10030202
Oesophageal ulcer haemorrhage
10052488
Oesophageal ulcer perforation
10030210
Oesophageal varices haemorrhage
10030219
Oesophagitis haemorrhagic
10049098
Oesophagitis ulcerative
10030860
Operative haemorrhage
10033645
Pancreatitis
10033647
Pancreatitis acute
10033649
Pancreatitis chronic
10033650
Pancreatitis haemorrhagic
10033654
Pancreatitis necrotizing
10033657
Pancreatitis relapsing
10069846
Patient-device incompatibility
10062065
Perforated ulcer
10034649
Peritoneal abscess
10067011
Peritoneal cloudy effluent
10061343
Peritoneal disorder
10058095
Peritoneal haematoma
10034666
Peritoneal perforation
10034674
Peritonitis
10062070
Peritonitis bacterial
10065326
Peritonitis helminthic
10034681
Peritonitis pneumococcal
10034684
Peritonitis syphilitic
10053418
Peritonitis viral
 


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Code
Preferred Term
10048299
Pneumoperitoneum
10068676
Pneumoretroperitoneum
10053174
Post procedural cellulitis
10058046
Post procedural complication
10068620
Post procedural constipation
10057585
Post procedural diarrhea
10057751
Post procedural discharge
10054126
Post procedural discomfort
10061489
Post procedural fistula
10063188
Post procedural haematoma
10051077
Post procedural haemorrhage
10067268
Post procedural infection
10066592
Post procedural myocardial infarction
10063645
Post procedural oedema
10066590
Post procedural pneumonia
10063909
Post procedural pulmonary embolism
10066593
Post procedural sepsis
10066591
Post procedural stroke
10066415
Post procedural swelling
10051182
Postoperative abscess
10054048
Postoperative ileus
10061468
Postoperative wound complication
10036410
Postoperative wound infection
10050173
Prepyloric stenosis
10057765
Procedural complication
10066962
Procedural nausea
10064882
Procedural pain
10036769
Procedural site reaction
10066963
Procedural vomiting
10069889
Product adhesion issue
10054981
Prophylaxis against gastrointestinal ulcer
10049863
Puncture site abscess
10063677
Puncture site infection
 


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Code
Preferred Term
10061926
Purulence
10037569
Purulent discharge
10038063
Rectal haemorrhage
10069839
Respiratory complication associated with device
10039003
Reversal of ileojejunal bypass
10040102
Seroma
10040893
Skin necrosis
10040943
Skin ulcer
10050377
Skin ulcer haemorrhage
10052535
Small intestinal haemorrhage
10041101
Small intestinal obstruction
10041103
Small intestinal perforation
10062263
Small intestinal stenosis
10061550
Small intestinal ulcer haemorrhage
10041133
Small intestine ulcer
10042070
Stitch abscess
10042128
Stomatitis
10050396
Subileus
10042618
Surgical procedure repeated
10044522
Traumatic haematoma
10053476
Traumatic haemorrhage
10067979
Traumatic liver injury
10044546
Traumatic ulcer
10045285
Ulcer
10061577
Ulcer haemorrhage
10070772
Unintentional medical device removal by patient
10046274
Upper gastrointestinal haemorrhage
10056091
Varices oesophageal
10069840
Vascular complication associated with device
10058042
Wound abscess
10054108
Wound evisceration
10048038
Wound infection
10065240
Wound infection bacterial
 


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Code
Preferred Term
10065242
Wound infection fungal
10065243
Wound infection helminthic
10059444
Wound infection pseudomonas
10059442
Wound infection staphylococcal
10065241
Wound infection viral
10070469
Wrong device dispensed
10070468
Wrong device used
10061582
X-ray gastrointestinal tract abnormal
10059691
X-ray with contrast lower gastrointestinal tract
10059705
X-ray with contrast lower gastrointestinal tract abnormal
10048210
X-ray with contrast upper gastrointestinal tract
2.
Polyneuropathy:  include Guillain-Barre syndrome SMQ (20000131) and 
peripheral neuropathy SMQ (20000034).
Guillain-Barre Syndrome SMQ (20000131)
Code
Preferred Term
Narrow Search (N)
10057645
Chronic inflammatory demyelinating polyradiculoneuropathy
N
10061811
Demyelinating polyneuropathy
N
10018767
Guillain-Barre syndrome
N
10049567
Miller Fisher syndrome
N
10049460
Abasia
10001052
Acute respiratory distress syndrome
10051224
Akinaesthesia
10059978
Albumin CSF increased
10002948
Aphasia
10003084
Areflexia
10003549
Asthenia
10003591
Ataxia
10070439
Autoimmune neuropathy
10003840
Autonomic nervous system imbalance
10061666
Autonomic neuropathy
 


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Code
Preferred Term
Narrow Search (N)
10003882
Axonal neuropathy
10049848
Balance disorder
10071641
Bell's phenomenon
10004846
Biopsy peripheral nerve abnormal
10049509
Brain stem auditory evoked response abnormal
10006542
Bulbar palsy
10007947
Central nervous system function test abnormal
10051290
Central nervous system lesion
10054937
Central nervous system mass
10010947
Coordination abnormal
10061093
Cranial nerve disorder
10011314
Cranial nerve palsies multiple
10061908
Cranial nerve paralysis
10064338
CSF immunoglobulin increased
10011562
CSF oligoclonal band present
10011573
CSF protein abnormal
10011575
CSF protein increased
10059703
CSF test abnormal
10067502
Decreased vibratory sense
10012305
Demyelination
10012725
Diaphragmatic paralysis
10013033
Diplegia
10013886
Dysaesthesia
10013887
Dysarthria
10013950
Dysphagia
10050256
Dysstasia
10014431
Electromyogram abnormal
10015727
Extensor plantar response
10051267
Facial paresis
10017577
Gait disturbance
10068912
Genital hypoaesthesia
10020937
Hypoaesthesia
10020939
Hypoaesthesia eye
 


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Code
Preferred Term
Narrow Search (N)
10057371
Hypoaesthesia oral
10051780
Hypoaesthesia teeth
10021021
Hypokinesia
10021089
Hyporeflexia
10071552
Hyporesponsive to stimuli
10021118
Hypotonia
10067068
Intranasal hypoaesthesia
10051660
Intranasal paraesthesia
10057332
Loss of proprioception
10025000
Lumbar puncture abnormal
10061296
Motor dysfunction
10065579
Multifocal motor neuropathy
10028289
Muscle atrophy
10028372
Muscular weakness
10029175
Nerve conduction studies abnormal
10056677
Nerve degeneration
10029192
Nerve stimulation test abnormal
10029323
Neuromyopathy
10071579
Neuronal neuropathy
10029331
Neuropathy peripheral
10030875
Ophthalmoplegia
10033712
Papilloedema
10033775
Paraesthesia
10033780
Paraesthesia mucosal
10058469
Paraesthesia of genital female
10052544
Paraesthesia of genital male
10057372
Paraesthesia oral
10033799
Paralysis
10033809
Paralysis flaccid
10033885
Paraparesis
10033892
Paraplegia
10033985
Paresis
10061911
Paresis cranial nerve
 


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Code
Preferred Term
Narrow Search (N)
10034580
Peripheral motor neuropathy
10067633
Peripheral nerve lesion
10058530
Peripheral nerve palsy
10034591
Peripheral nervous system function test abnormal
10054808
Peripheral paralysis
10056673
Peripheral sensorimotor neuropathy
10034620
Peripheral sensory neuropathy
10034701
Peroneal nerve palsy
10059923
Pharyngeal hypoaesthesia
10036105
Polyneuropathy
10036111
Polyneuropathy idiopathic progressive
10036800
Progressive bulbar palsy
10037114
Pseudobulbar palsy
10049680
Quadriparesis
10037714
Quadriplegia
10037779
Radiculopathy
10038254
Reflexes abnormal
10038669
Respiratory arrest
10038695
Respiratory failure
10070833
Respiratory muscle weakness
10038708
Respiratory paralysis
10062162
Sensorimotor disorder
10040026
Sensory disturbance
10048871
Sensory integrative dysfunction
10061567
Sensory level abnormal
10040030
Sensory loss
10041466
Speech disorder
10061551
Spinocerebellar disorder
10058560
Tandem gait test abnormal
10068008
Trigeminal nerve paresis
10049788
Trigeminal palsy
10045380
Ulnar neuritis
10045555
Unresponsive to stimuli
 


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Code
Preferred Term
Narrow Search (N)
10059101
Vibration test abnormal
10050040
VIIth nerve paralysis
10047641
VIth nerve paralysis
10071044
VIth nerve paresis
Peripheral Neuropathy SMQ (20000034)
Code
Preferred Term
Narrow Search (N)
10066699
Acute polyneuropathy
N
10002027
Amyotrophy
N
10070439
Autoimmune neuropathy
N
10003882
Axonal neuropathy
N
10004846
Biopsy peripheral nerve abnormal
N
10067502
Decreased vibratory sense
N
10061811
Demyelinating polyneuropathy
N
10018767
Guillain-Barre syndrome
N
10051307
Ischaemic neuropathy
N
10057332
Loss of proprioception
N
10049567
Miller Fisher syndrome
N
10065579
Multifocal motor neuropathy
N
10028570
Myelopathy
N
10029175
Nerve conduction studies abnormal
N
10029223
Neuralgia
N
10029240
Neuritis
N
10071579
Neuronal neuropathy
N
10029331
Neuropathy peripheral
N
10034580
Peripheral motor neuropathy
N
10034591
Peripheral nervous system function test abnormal
N
10056673
Peripheral sensorimotor neuropathy
N
10034620
Peripheral sensory neuropathy
N
10036105
Polyneuropathy
N
10064135
Polyneuropathy chronic
N
10036111
Polyneuropathy idiopathic progressive
N
 


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Code
Preferred Term
Narrow Search (N)
10068886
Radiation neuropathy
N
10062162
Sensorimotor disorder
N
10040026
Sensory disturbance
N
10040030
Sensory loss
N
10067722
Toxic neuropathy
N
10003084
Areflexia
10056339
Autonomic failure syndrome
10061666
Autonomic neuropathy
10070237
Burning feet syndrome
10006784
Burning sensation
10013886
Dysaesthesia
10014431
Electromyogram abnormal
10017062
Formication
10017577
Gait disturbance
10068912
Genital hypoaesthesia
10020937
Hypoaesthesia
10021089
Hyporeflexia
10021118
Hypotonia
10027910
Mononeuritis
10062203
Mononeuropathy
10027918
Mononeuropathy multiplex
10061296
Motor dysfunction
10028289
Muscle atrophy
10028372
Muscular weakness
10056677
Nerve degeneration
10062284
Neuromuscular toxicity
10029323
Neuromyopathy
10029332
Neuropathy vitamin B6 deficiency
10029350
Neurotoxicity
10033775
Paraesthesia
10067633
Peripheral nerve lesion
10058530
Peripheral nerve palsy
10071663
Peripheral nerve paresis
 


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Code
Preferred Term
Narrow Search (N)
10034699
Peroneal muscular atrophy
10034701
Peroneal nerve palsy
10064964
Phrenic nerve paralysis
10054786
Skin burning sensation
10068015
Temperature perception test decreased
10052492
Tinel's sign
10045380
Ulnar neuritis
3.
Weight loss (CMQ 80000109).
Code
Preferred Term
10000159
Abnormal loss of weight
10002647
Anorexia and bulimia syndrome
10002649
Anorexia nervosa
10060961
Appetite disorder
10005895
Body mass index decreased
10006895
Cachexia
10061428
Decreased appetite
10012775
Diet refusal
10013950
Dysphagia
10014062
Eating disorder
10061832
Eating disorder symptom
10050366
Fear of eating
10053050
Gastrointestinal tube insertion
10052592
Gastrostomy tube insertion
10063743
Hypophagia
10021577
Inadequate diet
10061273
Malnutrition
10026820
Marasmus
10028155
Multi-vitamin deficiency
10065026
Nutritional condition abnormal
10029861
Nutritional support
10051284
Parenteral nutrition
 


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Code
Preferred Term
10050086
Poor weight gain neonatal
10041954
Starvation
10048828
Underweight
10056814
Weight abnormal
10047894
Weight decrease neonatal
10047895
Weight decreased
10049040
Weight fluctuation
10047897
Weight gain poor
10047901
Weight loss diet
4.
Cardiovascular fatalities:  major adverse cardiovascular events (MACE) MI CMQ 
(80000076) and the outcome of the AE was fatal.
Code
Preferred Term
10051592
Acute coronary syndrome
10000891
Acute myocardial infarction
10054015
Agonal rhythm
10002388
Angina unstable
10003225
Arteriospasm coronary
10005468
Blood creatine phosphokinase abnormal
10005470
Blood creatine phosphokinase increased
10005472
Blood creatine phosphokinase MB abnormal
10005474
Blood creatine phosphokinase MB increased
10007515
Cardiac arrest
10049993
Cardiac death
10007548
Cardiac enzymes increased
10007617
Cardio-respiratory arrest
10007625
Cardiogenic shock
10050329
Coronary angioplasty
10052086
Coronary arterial stent insertion
10011077
Coronary artery bypass
10048631
Coronary artery dissection
10011084
Coronary artery embolism
 


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Code
Preferred Term
10052895
Coronary artery insufficiency
10011086
Coronary artery occlusion
10053261
Coronary artery reocclusion
10056489
Coronary artery restenosis
10011089
Coronary artery stenosis
10011091
Coronary artery thrombosis
10059025
Coronary bypass thrombosis
10011101
Coronary endarterectomy
10011105
Coronary ostial stenosis
10049887
Coronary revascularisation
10013428
Dissecting coronary artery aneurysm
10051177
Electrocardiogram Q wave abnormal
10014390
Electrocardiogram ST segment abnormal
10014392
Electrocardiogram ST segment elevation
10049225
Electrocardiogram ST-T segment elevation
10066846
In-stent coronary artery restenosis
10061216
Infarction
10070909
Metabolic cardiomyopathy
10028596
Myocardial infarction
10028600
Myocardial ischaemia
10051624
Myocardial reperfusion injury
10033697
Papillary muscle infarction
10065608
Percutaneous coronary intervention
10066592
Post procedural myocardial infarction
10058144
Postinfarction angina
10036759
Prinzmetal angina
10058151
Pulseless electrical activity
10061501
Scan myocardial perfusion abnormal
10040560
Shock
10049768
Silent myocardial infarction
10049418
Sudden cardiac death
10042434
Sudden death
10058268
Troponin I increased
 


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Code
Preferred Term
10058267
Troponin increased
10058269
Troponin T increased
10049060
Vascular graft occlusion
10047284
Ventricular asystole
10071186
Ventricular dyssynchrony
10047290
Ventricular fibrillation
10047294
Ventricular flutter
10065341
Ventricular tachyarrhythmia
10047302
Ventricular tachycardia
5.
Respiratory tract aspiration including aspiration pneumonia/pneumonitis 
(CMQ 80000103).
Code
Preferred Term
10066728
Acute interstitial pneumonitis
10069351
Acute lung injury
10001029
Acute pulmonary oedema
10001052
Acute respiratory distress syndrome
10001053
Acute respiratory failure
10002974
Apnoea
10002977
Apnoeic attack
10003497
Asphyxia
10003504
Aspiration
10050777
Aspiration bronchial
10003530
Aspiration tracheal
10003531
Aspiration tracheal abnormal
10003598
Atelectasis
10006102
Bradypnoea
10064913
Bronchial disorder
10006438
Bronchial irritation
10006440
Bronchial obstruction
10056695
Bronchial oedema
 


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Code
Preferred Term
10066820
Bronchial secretion retention
10051547
Bronchial ulceration
10067182
Bronchial wall thickening
10049413
Bronchoalveolar lavage
10063078
Bronchoalveolar lavage abnormal
10006469
Bronchopneumonia
10053582
Bronchopneumopathy
10053420
Bronchopulmonary disease
10006479
Bronchoscopy
10006480
Bronchoscopy abnormal
10008589
Choking
10008590
Choking sensation
10057482
Dependence on respirator
10060865
Duodenogastric reflux
10013950
Dysphagia
10013968
Dyspnoea
10013969
Dyspnoea at rest
10013971
Dyspnoea exertional
10067450
Endotracheal intubation
10063349
Endotracheal intubation complication
10052591
Enteral nutrition
10015894
Extubation
10056661
Feeding tube complication
10016985
Forced expiratory volume abnormal
10016987
Forced expiratory volume decreased
10017000
Foreign body aspiration
10017505
Functional residual capacity abnormal
10017508
Functional residual capacity increased
10053050
Gastrointestinal tube insertion
10064069
Gastrointestinal tube removal
10017885
Gastrooesophageal reflux disease
10052592
Gastrostomy tube insertion
10020591
Hypercapnia
 


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Code
Preferred Term
10020910
Hyperventilation
10020952
Hypocapnia
10021079
Hypopnoea
10021133
Hypoventilation
10021143
Hypoxia
10062530
Increased bronchial secretion
10062717
Increased upper airway secretion
10061257
Jaw disorder
10024378
Leukocytosis
10024738
Lobar pneumonia
10057260
Lower respiratory tract inflammation
10025080
Lung consolidation
10025082
Lung disorder
10025102
Lung infiltration
10026882
Mastication disorder
10049783
Mendelson's syndrome
10056652
Middle lobe syndrome
10058525
Nasal aspiration
10059841
Nasopharyngeal reflux
10049235
Nocturnal dyspnoea
10061877
Obstructive airways disorder
10056992
Oesophagobronchial fistula
10067472
Organising pneumonia
10031123
Orthopnoea
10058982
PCO2 abnormal
10034181
PCO2 decreased
10034193
Peak expiratory flow rate abnormal
10034195
Peak expiratory flow rate decreased
10067353
Pharyngeal disorder
10070912
Pharyngeal dyskinesia
10035664
Pneumonia
10035669
Pneumonia aspiration
10060946
Pneumonia bacterial
 


Levodopa-Carbidopa
S1873005 – Statistical Analysis Plan
Version 4.0 – 08 November 2016
120
Code
Preferred Term
10035730
Pneumonia primary atypical
10035742
Pneumonitis
10035745
Pneumonitis chemical
10062087
PO2 abnormal
10035768
PO2 decreased
10059184
Poor dental condition
10066590
Post procedural pneumonia
10036790
Productive cough
10037368
Pulmonary congestion
10037660
Pyrexia
10053307
Radiography guided aspiration
10067869
Reflux laryngitis
10062102
Removal of foreign body
10038330
Removal of foreign body from larynx
10038333
Removal of foreign body from oesophagus
10059390
Removal of foreign body from respiratory tract
10038334
Removal of foreign body from throat
10038647
Respiration abnormal
10038661
Respiratory acidosis
10038664
Respiratory alkalosis
10038669
Respiratory arrest
10038678
Respiratory depression
10038681
Respiratory depth decreased
10038682
Respiratory depth increased
10038683
Respiratory disorder
10038687
Respiratory distress
10038695
Respiratory failure
10052251
Respiratory tract congestion
10068956
Respiratory tract inflammation
10038731
Respiratory tract irritation
10070774
Respiratory tract oedema
10039109
Rhonchi
10050419
Sputum culture
 


Levodopa-Carbidopa
S1873005 – Statistical Analysis Plan
Version 4.0 – 08 November 2016
121
Code
Preferred Term
10051612
Sputum culture positive
10041807
Sputum discoloured
10041812
Sputum increased
10042241
Stridor
10042444
Suffocation feeling
10043089
Tachypnoea
10044291
Tracheal obstruction
10063968
Upper airway resistance syndrome
10052252
Upper respiratory tract congestion
10049590
Upper respiratory tract inflammation
10070841
Upper respiratory tract irritation
10069555
Use of accessory respiratory muscles
10047924
Wheezing