Clinical trial NCT02549092
Conditions: Advanced Parkinson's Disease
Keywords: levodopa-carbidopa intestinal gel levodopa carbidopa Advanced Parkinson's Disease Non-Motor Symptom Scale NMSS Parkinson's Disease Sleep Scale PDSS-2 efficacy
Sponsor: AbbVie
Start date: 2015-10-26; Completion date: 2022-11-18
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to examine the effect of LCIG relative to that of OMT on NMS associated with PD.

Detailed description:
The study will consist of 3 sequential parts:

Part 1: Screening period. The screening period will consist of 3 visits, Visit 1 (V1), Visit 2 (\[V2\] \[optional\]) and the Randomization Visit (V3) in which the participant will be assessed to determine eligibility. The duration of the Screening Period can be between 30 to 67 days to accommodate the required procedures, training and collection of diaries, and to allow for stabilization of anti-PD medications and medications to treat NMS. All anti-PD medications and medications to treat NMS are required to be stable for a minimum of 30 days prior to randomization.

Part 2: Treatment period. Those participants randomized to OMT at the end of V3 will remain on their current optimized regimen. The day after randomization will be considered Day 1 of their treatment period and participants will have study visits at the end of Weeks 2, 6, 12, and 26. All participants randomized to the LCIG group should have all anti-PD medications, with the exception of levodopa formulations, tapered off within 14 days after randomization. Optional nasojujunal (NJ) and/or percutaneous endoscopic gastrostomy with a jejunal tube (PEG-J) placement will then occur. After that, the participant may begin initiation and titration of LCIG infusion to be adjusted to obtain the optimal clinical response. The day of initial NJ or PEG-J placement will be considered Day 1 for participants in the LCIG group. Study visits happen at the end of Weeks 2, 6, 12, and 26.

Part 3: Extension/Transition Period. Eligible participants who complete the 26 week study may continue into the Extension Period of the study. Participants in the LCIG arm will have study drug dispensation every 4 weeks and will have study visits every 6 months. Participants from the OMT arm will undergo the NJ (optional) and PEG-J procedures, titration, plus have visits at 2 weeks, 6 weeks, 3 months and 6 months post NJ or PEG-J. Participants will then continue to receive study drug every 4 weeks and will have study visits every 6 months until Duodopa is commercially available. Transition to a Post-Trial Access protocol will be possible if Duodopa does not become commercially available in a location.

Arms: arm 1: Participants randomized to continue OMT remain on their current optimized regimen. During the 26-week treatment phase, changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated.

Eligible participants may elect to enter an extension/transition follow-up period to receive an individually optimized LCIG dose (after NJ and/or PEG-J placement), in order to transition to commercially available LCIG. arm 2: Participants randomized to LCIG at an individually optimized dose (after NJ and/or PEG-J placement), in accordance with the LCIG approved product label for countries participating in the study. During the 26-week treatment phase, changes to anti-PD and NMS medications are to remain stable and can only be made if medically indicated.

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

Eligible participants may elect to enter an extension/transition follow-up period to receive an individually optimized LCIG dose, in order to transition to commercially available LCIG.
Interventions: intervention 1: Optimized Medical Treatment intervention 2: Levodopa-Carbidopa Intestinal Gel intervention 3: Nasojejunal (NJ) tube intervention 4: Percutaneous endoscopic gastrostomy with a jejunal (PEG-J) tube
Intervention descriptions: intervention 1: Oral, sublingual or transdermal anti-PD medications and medications to treat NMS per Investigator discretion and/or in accordance with approved product label of the prescribed medications. intervention 2: None intervention 3: optional prior to PEG-J placement intervention 4: None

Protocol documents:
Prot_000.pdf: 
Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
1
1.0
Title Page
Clinical Study Protocol M12-927
An Open-label, Randomized 26-Week Study 
Comparing Levodopa-Carbidopa INteStInal Gel 
(LCIG) THerapy to Optimized Medical Treatment 
(OMT) on Non-Motor Symptoms (NMS) in Subjects 
with Advanced Parkinson's Disease –
INSIGHTS Study
Incorporating Administrative Changes 1, 2 and 
Amendments 1, 2, 3, and 4
AbbVie Investigational
  Product:
Levodopa-Carbidopa Intestinal Gel (LCIG)
Date:
31 May 2017
Development Phase:
3b
Study Design:
A Phase 3b, open-label, multicenter 26-week study comparing 
LCIG to optimized medical treatment on non-motor symptoms 
associated with advanced Parkinson's disease.
EudraCT Number:
2014-004865-26
Investigator:
Investigator information on file at AbbVie
Sponsor:
AbbVie
Sponsor/Emergency 
  Contact:
AbbVie
1 North Waukegan Road, 
North Chicago, IL  60064
Phone:
Mobile:
Fax:
This study will be conducted in compliance with the protocol, Good Clinical Practice ICH-GCP E6(R1) and 
all other applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02549092


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
23 January 2015
Amendment 1
21 May 2015
Administrative Change 1
27 October 2015
Amendment 2
28 March 2016
Amendment 3
15 November 2016
Administrative Change 2
16 March 2017
The purpose of this amendment is to:
●
Change the study Reference Safety Information (RSI) from the Duodopa 
Summary of Product Characteristics (SmPC) to the Levodopa-Carbidopa 
Intestinal Gel (LCIG), (also known as Duopa or Duodopa) Investigator 
Brochure (IB).
Rationale:  This change was made to align the study with AbbVie's Standard 
Operating Procedures (SOPs).
Throughout the protocol changes were made to update language per the new protocol 
template, correct typographical errors, and provide clarity.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix E.


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M12-927
Name of Study Drug:  Levodopa-Carbidopa 
intestinal gel (SLV-187)
Phase of Development:  3b
Name of Active Ingredient:  Levodopa-Carbidopa 
Date of Protocol Synopsis:  31 May 2017
Protocol Title:  
An Open-label, Randomized 26-Week Study Comparing Levodopa-Carbidopa INteStInal Gel (LCIG) 
THerapy to Optimized Medical Treatment (OMT) on Non-Motor Symptoms (NMS) in Subjects with 
Advanced Parkinson's Disease – INSIGHTS Study
Objectives:  
Primary
The primary objective of this study is to examine the effect of LCIG relative to that of OMT on 
non-motor symptoms associated with advanced Parkinson's disease (PD) as assessed by the Non-Motor 
Symptoms Scale (NMSS) Total Score and the Modified Parkinson's Disease Sleep Scale (PDSS-2) Total 
Score.
Secondary
To assess the effect of LCIG relative to that of OMT on the motor symptoms/motor complications, 
safety, tolerability and health-related outcome measures.
Motor symptoms/motor complications will be measured by:
!
Unified Parkinson's Disease Rating Scale (UPDRS) Parts III and IV
Safety and tolerability will be assessed by:
!
Adverse event monitoring
!
Neurological exams
!
Clinical laboratory evaluations
!
Electrocardiogram
!
Vital signs and weight
!
Columbia Suicide Severity Rating Scale (C-SSRS)
!
Minnesota Impulsive Disorders Interview (MIDI)
!
Sleep Attacks Questionnaire (SAQ)
Health Related Outcomes will be measured by:
!
Parkinson's Disease Questionaire-8 (PDQ-8)
!
Clinical Global Impression of Change (CGI-C)
!
UPDRS Parts I and II
!
Patient Global Impression of Change (PGIC)
!
Parkinson Anxiety Scale (PAS)
!
Geriatric Depression Scale (GDS-15)
!
King's Parkinson's Disease (PD) Pain Scale
Investigators:  Multi-center


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Study Sites:  This study will be conducted at approximately 40 – 50 sites in approximately 10 countries 
worldwide
Study Population:  
Levodopa-responsive Parkinson's disease patients with severe motor fluctuations and 
hyperkinesia/dyskinesia when available combinations of Parkinson medicinal products have not given 
satisfactory results.
Number of Subjects to be Enrolled:  Approximately 88 subjects (44 per each treatment group)
Methodology:  
Figure 1:  Study Design Schematic
This is a Phase 3b, open-label, randomized multicenter 26-week study comparing LCIG to optimized 
medical treatment (OMT).  The study will consist of 3 sequential periods:  Screening, Treatment and 
Follow-Up.  The OMT group will have the same schedule of visits/procedures throughout the study as 
the LCIG group except for visits related to NJ/PEG procedures and titration of LCIG. 


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
5
Methodology (Continued):
The Screening Period (V1 – V3)
The Screening Period will be the same for all subjects screened into the study.  The Screening Period will 
consist of three visits, Visit 1 (V1), Visit 2 ([V2] [optional]) and the Randomization Visit (V3) in which 
the subject will be assessed to determine eligibility.  A movement disorder specialist should perform an 
interview of the subject at screening.  The duration of the Screening Period can be between 30 – 67 days 
to accommodate the required procedures, training and collection of diaries, and allow for stabilization of 
anti-PD medications and medications to treat NMS.  All anti-PD medications and any other medications 
used to treat individual non-motor symptoms (e.g., Insomnia, depression, anxiety), must be stable with no 
adjustments to the frequency of administration, dose of administration or total daily dose.  Both anti-PD 
medications and medications to treat NMS are required to be stable for a minimum of 30 days.  During 
the Screening Period, no study drug (LCIG) will be administered.  Visit 2 is optional and is based on the 
PIs discretion of individual subject need during stabilization of anti-PD medications and medications to 
treat NMS.  Subjects who are deemed eligible by randomization criteria at Visit 3 will be randomized at 
the end of Visit 3 to receive LCIG or continue on OMT following baseline assessments.
Treatment Period (V4 – V8)
OMT Group:
Those subjects randomized to continue OMT will remain on their current optimized regimen and will 
have study visits at the end of Weeks 2, 6, 12, and 26 following randomization (V3).  The OMT group 
will not have a V4 (NJ/PEG-J Placement).  The day after randomization (V3) will be considered Day 1 of 
their treatment period.
During the treatment phase, changes to anti-PD and NMS medications should remain stable and can only 
be made if medically indicated.  Changes to the OMT arm can be made "if medically justified," not only 
for serious safety reasons.
LCIG Group:
In accordance with the LCIG approved Product Label for countries participating in the study, those 
subjects randomized to LCIG must discontinue all other anti-PD medications (e.g., dopamine agonists, 
COMT-inhibitors, amantadine, MAO-B inhibitors, anti-cholinergics, and subcutaneous apomorphine 
etc.) prior to LCIG initiation on Day 1 (V4); these medications should be tapered off according to the 
prescribing information and the discretion of the Investigator.  With the exception of continuous 
subcutaneous delivery of apomorphine or levodopa containing formulations, these medications may be 
restarted if indicated by the subject's individual condition, but not within the first 28 days after LCIG 
initiation.
For those subjects randomized to LCIG, an optional, temporary nasojejunal (NJ) tube may be used 
initially to titrate the dose of LCIG.  Following the NJ phase, a percutaneous endoscopic gastrostomy 
with a jejunal tube (PEG-J) will be performed by a gastroenterologist proceduralist.  Total time to 
titration via the NJ and PEG-J should not exceed 14 days.  Alternatively, subjects may proceed directly to 
placement of the permanent PEG-J tube without the NJ phase at the discretion of the principal 
investigator.  If the subject proceeds directly to PEG-J, titration should be completed within 7 days.  
However, at the PI's discretion additional days of optimization may be made if indicated.  Subjects on 
LCIG will return for study visits at the end of Weeks 2, 6, 12, 26 and 27 following PEG-J placement. 


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Methodology (Continued):
LCIG Group (Continued):
Subjects and/or caregivers must come into the clinic or pharmacy between V7 (Week 12) and V8 
(Week 26) for clinical LCIG return and supply visits so that there is no risk of medication expiring.  The 
drug dispensing visits will occur at Weeks 17 and 22 (± 7 days).  Other assessments may be completed 
during these visits if required.
During the treatment phase, medications used to treat specific non-motor symptoms must remain stable 
for the duration of the study unless medically warranted.
Study Follow-Up
The OMT subjects will not have a follow-up visit (V9).
For LCIG subjects who elect to discontinue LCIG and not continue with commercially available product, 
a V9 will be conducted one week after NJ/PEG-J removal and the follow-up period will be up until 
30 days after NJ/PEG-J removal.  For LCIG subjects who will transition to commercial product, the 
SAE/AE follow-up period will be 30 days after conversion to commercial.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Subject must have a diagnosis of idiopathic Parkinson's disease according to the United Kingdom 
Parkinson's Disease Society (UKPDS) Brain Bank Criteria.  See Appendix C for UKPDS.
2.
Subject demonstrates persistent motor fluctuations in spite of individually optimized treatment.
3.
The subject's Parkinson's disease is levodopa-responsive.
4.
Subject has had optimal treatment with available anti-PD medication and their motor symptoms are 
judged inadequately controlled on this optimized treatment.  Optimized treatment is defined as the 
maximum therapeutic effect obtained with pharmacological antiparkinsonian therapies when no 
further improvement is expected regardless of any additional manipulations of levodopa and/or other 
antiparkinsonian medication.  This will be based on the Investigator's clinical judgment.
5.
Subject and/or if applicable, their care-partner must be able to complete the Subject Dosing Diary 
and must be able to demonstrate the ability to operate, manipulate and care for the infusion pump and 
tubing.
6.
Subject is eligible to transfer to commercial treatment of Duodopa after completing the study based 
on local country requirements.
7.
Subject must have a minimum PDSS-2 total score of 18 at Baseline assessment.*
8.
Subject must be able to understand the nature of the study and has had the opportunity to have any 
questions answered.  Prior to the conduct of any study procedures (including any changes occurring 
in the subject's current therapeutic regimen), the subject, if judged by the PI to have decision making 
capacity, must have voluntarily signed the Independent Ethics Committees/Institutional Review 
Board (IEC/IRB) approved Informed Consent.  In the absence of subject's ability to provide the 
informed consent, the informed consent must have been signed by a person who has the legal right to 
act on behalf of the subject following national laws
9.
Male or female subjects at least 30 years of age.


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):
10. If female, subject must be either postmenopausal, OR permanently surgically sterile OR for Women 
of Childbearing Potential practicing at least one protocol specified method of birth control, starting at 
Study Day 1 through at least 30 days after the last dose of study drug.
If the male subject is sexually active with female partner(s) of childbearing potential, he must agree, 
from Study Day 1 through 4 weeks after the last dose of study drug, to practice the protocol specified 
contraception.
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and 
a negative urine pregnancy test at Study Day 1.
12. Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined above) at Screening do not require pregnancy testing.
*
If previously excluded because of this inclusion criterion, subject is eligible to re-screen.
Main Exclusion:  
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1.
Subject's PD diagnosis is unclear or there is a suspicion that the subject has a parkinsonian syndrome 
such as secondary parkinsonism (e.g., caused by drugs, toxins, infectious agents, vascular disease, 
trauma, brain neoplasm), parkinson-plus syndrome (e.g., Multiple System Atrophy, Progressive 
supranuclear Palsy, Diffuse Lewy Body disease) or other neurodegenerative disease that might 
mimic the symptoms of PD.
2.
Subject has undergone neurosurgery for the treatment of Parkinson's disease.
3.
Subject has discontinued apomorphine continuous infusion for the treatment of Parkinson's disease 
less than 3 months prior to screening visit.
4.
Subject has any neurological deficit that might interfere with the study assessments 
(e.g., hemiparesis).
5.
Known hypersensitivity to levodopa, carbidopa or radiopaque material.
6.
Subject has contraindications to levodopa, (e.g., narrow angle glaucoma, malignant melanoma).
7.
Subject experiencing clinically significant sleep attacks or clinically significant impulsive behavior 
(e.g., pathological gambling, hypersexuality) at any point during the three months prior to the 
Screening evaluation) as judged by the Investigator.
8.
Current diagnosis or history of drug or alcohol abuse (DSM-V-TR criteria) within 12 months prior to 
screening visit.
9.
Current primary psychiatric diagnosis of uncontrolled acute psychotic disorder or primary psychiatric 
diagnoses of bipolar disorder, schizophrenia, obsessive compulsive disorder or currently 
experiencing a major depressive episode with psychotic features per Diagnostic and Statistical 
Manual of Mental Disorders Fourth Edition, Text Revision (DSM-V-TR).
10. Currently experiencing or any known history of psychosis (e.g., troublesome hallucinations with or 
without insight) or delusions within 3 months prior to Screening.
11. A Mini-Mental State Examination (MMSE) score of < 24 or significant cognitive impairment that, in 
the opinion of the Investigator, could impact the subject's ability to participate in the trial.


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):
12. Serum glutamic-oxaloacetic transaminase (AST) or serum glutamic-pyruvic transaminase (ALT) 3 × 
the upper limit of normal (ULN), or any abnormal laboratory value that is considered clinically 
significant by the Investigator or could interfere with safety assessments.
13. Current evidence of clinically significant hematological, autoimmune, endocrine, cardiovascular, 
renal or gastrointestinal disorder that would possibly interfere with the subject's participation in the 
study (e.g., treated and controlled stable hypertension would not be considered an Exclusion).
14. Subject has current or a history of gastrointestinal, liver, kidney or other condition which may 
interfere with the absorption, distribution, metabolism or excretion of the study drug (e.g., gastric or 
intestinal surgery).
15. Any malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma of the skin 
within the past five years prior to Screening.  Subjects with prostate cancer or completely excised 
squamous cell carcinoma of the skin without reoccurrence within two years prior to Screening may 
be permitted to enroll following Investigator and study designated physician discussion and 
documentation of approval.  No history of antineoplastic and immunosuppressants administered for 
cancer treatment (within last 5 years).  Note:  Biopsy and diagnosis must be completed for any 
suspicious lesion at dermatology or physical exam.
16. A planned surgical procedure scheduled when the subject would be participating in this study.  
Subject may subsequently be considered for the study following full recuperation from the surgical 
procedure.
17. Exposure to any investigational drug within 30 days prior to Screening.
18. Previous enrollment in this study, any other LCIG study or any prior exposure to LCIG.
19. Current enrollment in another clinical study.
20. Subject for whom the placement of a PEG-J tube for LCIG treatment is contraindicated or is 
considered a high risk for the PEG-J procedure according to the gastroenterology evaluation.
21. Subject has significant current suicidal ideation within one year prior to Screening as evidenced by 
answering "yes" to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) completed at Screening or a history of suicidal attempts within the last 
2 years.
22. A low B12 level or low-normal B12 level (less than 300 pg/mL) with elevated methylmalonic acid 
(MMA) at Screening Visit 1.*
23. Positive screen for drugs of abuse or medical marijuana at Screening Visit 1.
24. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to 
receive LCIG.
25. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study 
or for approximately 30 days after the last dose of study drug.
26. Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 30 days after the last dose of study drug.
*
If treated and repeat labs confirm levels rise above 300 pg/mL, subject is eligible to re-screen.


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Investigational Products:
Levodopa (20 mg/mL) and Carbidopa monohydrate (5 mg/mL) in an 
aqueous intestinal gel (carboxymethylcellulose) dispensed in a 
medication cassette reservoir of 100 mL.
Devices are listed below but are not limited to:
Devices in LCIG System
Description
Manufacturer
Pump CADD Legacy 1400
Smiths Medical
NJ Tube
AbbVie or Covidien
Safety Adapter
Vygon
Extension Tube FR
Vygon
PEG Tube
AbbVie
Intestinal Tube
AbbVie
Y-Adapter for PEG Tube
AbbVie
Click Adapter for PEG Tube
AbbVie
Doses:
LCIG:  For those randomized to LCIG, each subject's dose will be 
individually optimized in accordance with the LCIG approved product 
label for countries participating in the study.  The dose should be 
adjusted to an optimal clinical response for the individual patient, which 
means maximizing the functional ON-time during the day by 
minimizing the number and duration of OFF episodes (bradykinesia) 
and minimizing ON-time with disabling dyskinesia. 
Once optimized, dose adjustments to LCIG can be made up to Day 28.  
After Day 28 the dose should remain stable for the duration of the study 
unless adjustments are absolutely needed for safety reasons.  If 
modifications are needed, this should first be discussed with the medical 
monitor.
The total daily dose of LCIG will be composed of three components:  
(i) the morning dose, (ii) continuous maintenance infusion dose and 
(iii) extra doses.  The continuous infusion is expected to run over a 
period of 16 consecutive hours each day.
Mode of Administration:
LCIG is dispensed in a medication cassette reservoir of 100 mL, 
designed to be connected to a portable subject-operated pump for 
infusion via NJ or PEG-J.
Reference Therapy:
Optimized Medical Treatment
Doses:
PI discretion and/or in accordance with approved product label of the 
prescribed medications
Mode of Administration:
Oral, sub-lingual or transdermal
Duration of Treatment:  26 weeks


Levodopa-Carbidopa Intestinal Gel
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EudraCT 2014-004865-26
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Criteria for Evaluation:
Efficacy:
There will be two alternative primary efficacy variables.
!
Change from baseline to Week 26 in NMSS total score
!
Change from baseline to Week 26 in PDSS-2 total score
Key secondary endpoints will consist of the following validated scales:
!
PDQ-8 summary index
!
CGI-C
!
UPDRS Part II score
Health Outcome will be assessed by the following measurements that are part of the secondary endpoints:
!
PDQ-8
!
CGI-C
!
UPDRS Parts I and II
!
PGIC
!
PAS
!
GDS-15
!
King's PD Pain Scale
Safety:
Safety and tolerability over the course of the study will be assessed by the following measurements:
!
Adverse event monitoring
!
Neurological exams
!
Clinical laboratory evaluations
!
Electrocardiogram
!
Vital signs and weight
!
C-SSRS
!
MIDI
!
SAQ
Statistical Methods:
Efficacy:
Efficacy Dataset and Treatment Period
The efficacy analysis will be performed on the intent-to-treat dataset which will include all subjects who 
are randomized to the optimized medical treatment, and all subjects who are randomized to LCIG and 
received at least one dose of study drug.  For assessments of efficacy the treatment period will begin the 
day after randomization (V3) for subjects randomized to OMT, and the day of first LCIG infusion 
following PEG-J placement for subjects randomized to LCIG treatment.  The treatment period will end 
on the day of the final visit for subjects randomized to OMT, and on the last day of LCIG study drug 
infusion for subjects randomized to LCIG treatment.  The last assessment prior to randomization will be 
considered baseline and the last assessment that is no more than 2 days after the end of the treatment 
period will be considered the final evaluation.


Levodopa-Carbidopa Intestinal Gel
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EudraCT 2014-004865-26
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Statistical Methods (Continued):
Efficacy (Continued):
Primary Efficacy Analysis
There are 2 alternative primary efficacy variables, change from baseline to Week 26 for NMSS total 
score and change from baseline to Week 26 for PDSS-2 total score.  Either variable considered 
statistically significant after multiplicity adjustment is sufficient to declare success of the study.
The primary efficacy analysis model is a likelihood-based mixed-effects model repeated measures 
(MMRM) analysis of the change from baseline for each post-baseline observation using all observed 
data.  The model will include fixed, categorical effects for treatment, site, visit, and treatment-by-visit 
interaction, with continuous fixed covariates for baseline score and the baseline score-by-visit interaction.  
The primary comparison will be the contrast between LCIG and optimized oral treatment at the Week 26 
Visit.
The two-sided P values obtained from the MMRM model for NMSS total score change from baseline to 
Week 26 and PDSS-2 total score change from baseline to Week 26 will be adjusted for multiplicity using 
the Hochberg procedure.  This method controls the family-wise error rate (FWER) at a pre-specified 
significance level (alpha = 0.05).  Specifically, the following steps will be followed:
!
If the larger of the 2 P values is ≤ 0.05 (i.e., both P values are ≤ 0.05), both endpoints are 
considered statistically significant.
!
If the larger of the 2 P values is > 0.05, then compare the smaller P value with 0.025.  The 
second endpoint is statistically significant if the P value is ≤ 0.025; otherwise, neither endpoint 
is considered statistically significant.
Secondary Efficacy Analyses
There are 3 key secondary endpoints:
!
PDQ-8 summary index
!
CGI-C
!
UPDRS Part II score
The key secondary efficacy endpoints will be analyzed with the same MMRM model as the primary 
efficacy variables.  For CGI-C, the scores collected at the visits will be the dependent variable.
If both primary efficacy variables are statistically significant after adjusting for multiplicity, the Stepwise 
Gatekeeping Procedure will be utilized and the 3 key secondary endpoints will be tested using the 
Hochberg procedure with significance level of 0.05.
Other secondary endpoints below will be analyzed with the same MMRM model as the primary efficacy 
variables:
!
NMSS domain scores
!
PDSS-2 domain scores
!
UPDRS total score, Part I score, Part III score, Part IV score
!
PGIC
!
Parkinson Anxiety Scale (PAS) total and subscale scores
!
Geriatric Depression Scale (GDS-15) score
For the analysis on PGIC, the scores collected at the visits will be the dependent variable.


Levodopa-Carbidopa Intestinal Gel
M12-927 Protocol Amendment 4
EudraCT 2014-004865-26
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Statistical Methods (Continued):
Safety:
Safety Dataset and Treatment Period
All safety analyses will be performed on the safety dataset which will include all subjects who are 
randomized to the optimized medical treatment, and all subjects who are randomized to LCIG and 
received at least one dose of study drug.  The treatment period for safety is the same as what is defined 
for efficacy.
Safety Analyses
Safety analyses will include summaries of adverse events, device-related product complaints, vital signs 
and special labs.
Determination of Sample Size
Approximately 88 subjects will be enrolled into the study and randomized in a 1:1 ratio to either OMT or 
LCIG.  There are no results on NMSS or PDSS-2 available from randomized trials comparing LCIG and 
OMT.  Interim data from ongoing Phase 3b Study M12-920 showed that the improvement in NMSS total 
score from baseline to Week 12 is 24.8 in the LCIG arm with standard deviation of 24.  Results from 
Zibetti et al (2013) showed that the improvement in PDSS-2 total score after an average of 3.5 months of 
LCIG treatment was 13.1.  The standard deviation was not provided and is estimated to be 12.2 assuming 
the correlation between baseline and follow-up visits is 0.5.
The significance level for this study is 0.05.  For sample size determination, it is assumed that the 
improvement in the OMT group is 33% of the LCIG group, i.e., the improvement is 8.2 on NMSS total 
score and 4.3 on PDSS-2 total score, and that the correlation between these 2 measures is 0.5, Simulation 
showed that a study with 37 subjects per group will have 90% power to declare statistical significance on 
at least one of these 2 alternative primary endpoints after multiplicity adjustment using Hochberg 
procedure.  It is further assumed that 10% of randomized subjects in either treatment group will not 
provide post-randomization efficacy assessment.  Additional simulations showed that 44 subjects per 
group will provide 90% power in the sensitivity analysis using baseline observation carried forward for 
subjects without post-randomization assessment.  Therefore the total planned enrollment is decided to be 
88 subjects.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
adverse event
AESI
adverse event of special interest
β-HCG 
beta-human chorionic gonadotropin
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CGI-C
Clinical Global Impression – Change 
CHMP
Committee for Medicinal Products for Human Use
CMQ
Company MedDRA Query
CNE or DSS
Clinical Nurse Educator – Duodopa Study Specialist
COMT
Catechol O methyltransferase
CR
controlled release
CS
Clinically Significant
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events 
DBP
diastolic blood pressure
DBS
Deep Brain Stimulation
DDI
DOPA decarboxylase inhibitor
DO
Doctor of Osteopath
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSS
Duodopa Study Specialist
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic case report form
EQ VAS
EuroQol Visual Analogue Scale 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GDS-15
Geriatric Depression Scale
GDSM
Global Drug Supply Management
GI
gastro-intestinal
GMP
Good Manufacturing Practice
HLGT
high level group term


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HLT
high level term
HRQoL
health related quality of life 
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 Application
IV
Intravenous
IR
Immediate Release
IRB
Institutional Review Board
IRT
Interactive Response Technology 
LAR
Legally acceptable representative
LCIG
levodopa-carbidopa intestinal gel
LC-CR
Levodopa/Carbidopa-Continuous Release
LC-IR
Levodopa/Carbidopa-Immediate Release
LLT
lowest level term
MAO-A
monoamine oxidase A
MAO-B
monoamine oxidase B
MAO Inhibitors
monamine oxidase inhibitors
Max
Maximum
MD
Doctor of Medicine
MedDRA
Medical Dictionary for Regulatory Activities
MIDI
Minnesota Impulsive Disorders Interview
Min
Minimum
MMA
methylmalonic acid
MMSE
Mini-Mental State Examination
MMRM
Mixed-effect Repeated-Measures Model
MoCA
Montreal Cognitive Assessment
NCS
Not Clinically Significant
NDC
National Drug Code
N-J
Nasojejunal
NMS
Non-motor symptoms
NMSS
Non-Motor Symptom Scale
NP
Nurse Practitioner
NONMEM®
nonlinear mixed effects modeling


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3-OMD
3-O-methyldopa
OMT
Optimized Medical Therapy
PA
Physician Assistant
PAS
Parkinson Anxiety Scale
PC
Product Complaints
PCS
Potentially Clinically Significant 
PD
Parkinson's disease
PDQ-8
Parkinson's Disease Questionnaire-8
PDQ-39
Parkinson's Disease Questionnaire-39
PDSS-2
Parkinson's Disease Sleep Scale
PEG
percutaneous endoscopic gastrostomy
PEG-J
percutaneous endoscopic gastrostomy – with jejunal extension
PGIC
Patient Global Impression of Change
PhD
Doctor of Philosophy
PK
Pharmacokinetic
PLMS
periodic limb movements of sleep 
PT
preferred term
QoL
Quality of Life
RBD
behavioral sleep disorder
REM
rapid eye movement 
RLS
restless leg syndrome
RSI
Reference Standard Information
SAP
Statistical Analysis Plan
SAQ
Sleep Attacks Questionnaire
SBP
systolic blood pressure
SD
standard deviation
SGOT/AST
aspartate aminotransferase
SGPT/ALT
alanine aminotransferase
SmPC
Summary of Product Characteristics
SMQ
Standard MedDRA Query
SOC
system organ class
SOP
standard operating procedure
TA MD
Therapeutic Area Medical Director
UKPDS
United Kingdom Parkinson's Disease Society


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UPDRS
Unified Parkinson's Disease Rating Scale
WHO
World Health Organization
WOCBP
Women of Child Bearing Potential
Definition of Terms
Dose Titration Diary
A paper record used to document the date, time and dose changes during 
subject titration.
Duodopa Study Specialist
An external nurse specialist who may be provided by the Sponsor to 
assist the Investigator with initiation and titration of LCIG.
LCIG Cassette Use Form
A paper record used to document dates of individual LCIG cassette use.
LCIG Optimization
Following the introduction of LCIG, maximizing the functional "On" 
time and minimizing the number of "Off" (bradykinesia) episodes 
during the day and the total time the subject is "Off;" in addition, 
minimizing the "On" time with troublesome dyskinesia.
LCIG Prescription Record
A paper record of the LCIG pump settings for a subject's morning dose, 
flow rate and extra doses that is recorded at every visit by the site.
Optimized Treatment
The maximum therapeutic effect obtained with pharmacological 
antiparkinsonian therapies when no further improvement is expected 
regardless of any additional manipulations of levodopa and/or other 
antiparkinsonian medication.
PRN
Per Diem or As Needed.
Subject Dosing Worksheet
A paper record used to document the date, time and dose of LCIG and 
levodopa-carbidopa tablets used by the subject during the initial titration 
period.
Subject Dosing Diary
A paper record used to document the date, time and dose of either 
(i) LCIG and levodopa-carbidopa tablets used by the subject during the 
study, after initial titration or (ii) all anti-PD medications taken during 
the study, depending on randomized treatment arm.


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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................................................................................................. 3
1.3
List of Abbreviations and Definition of Terms...................................... 13
2.0
Table of Contents ................................................................ 17
3.0
Introduction......................................................................... 22
3.1
Differences Statement .......................................................................... 30
3.2
Benefits and Risks................................................................................ 30
4.0
Study Objective ................................................................... 33
5.0
Investigational Plan.............................................................34
5.1
Overall Study Design and Plan:  Description ........................................ 34
5.1.1
Screening Period .................................................................................. 35
5.1.2
The Treatment Period........................................................................... 38
5.1.2.1
OMT Group ......................................................................................... 38
5.1.2.2
LCIG Treatment Group ........................................................................ 38
5.1.3
Study Follow-Up.................................................................................. 42
5.2
Selection of Study Population............................................................... 43
5.2.1
Inclusion Criteria.................................................................................. 43
5.2.2
Exclusion Criteria................................................................................. 45
5.2.3
Prior and Concomitant Therapy............................................................ 49
5.2.3.1
Prior Therapy (Prior to Randomization)................................................ 49
5.2.3.2
Concomitant Therapy........................................................................... 49
5.2.3.3
Rescue Therapy (LCIG Group Only).................................................... 54
5.2.3.4
Post Infusion Night Time Therapy (LCIG Group Only)........................ 54
5.2.3.5
Contraception Recommendations ......................................................... 54
5.3
Efficacy and Safety Assessments/Variables.......................................... 56
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 56
5.3.1.1
Study Procedures.................................................................................. 62
5.3.1.2
Rater Requirements.............................................................................. 79
5.3.1.3
Ancillary Support................................................................................. 81
5.3.2
Drug Concentration Measurements....................................................... 82


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5.3.3
Efficacy Variables................................................................................ 82
5.3.4
Safety Variables ................................................................................... 83
5.3.5
Health Outcome Variables.................................................................... 83
5.4
Removal of Subjects from Therapy or Assessment ............................... 84
5.4.1
Discontinuation of Individual Subjects ................................................. 84
5.4.2
Removal of the PEG-J (LCIG Group Only) .......................................... 85
5.4.3
Discontinuation of Entire Study............................................................ 85
5.5
Treatments ........................................................................................... 86
5.5.1
Treatments Administered...................................................................... 86
5.5.1.1
OMT .................................................................................................... 86
5.5.1.2
LCIG.................................................................................................... 86
5.5.2
Identity of Investigational Product........................................................ 92
5.5.2.1
Investigational Product and Supplies .................................................... 92
5.5.2.2
Packaging and Labeling........................................................................ 93
5.5.2.3
Storage and Disposition of Study Drug................................................. 93
5.5.3
Method of Assigning Subjects to Treatment Groups............................. 94
5.5.4
Selection and Timing of Dose for Each Subject.................................... 94
5.5.5
Blinding ............................................................................................... 95
5.5.6
Treatment Compliance ......................................................................... 95
5.5.7
Drug Accountability............................................................................. 95
5.5.8
Device Accountability.......................................................................... 96
5.6
Discussion and Justification of Study Design........................................ 97
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 97
5.6.2
Appropriateness of Measurements........................................................ 97
5.6.3
Suitability of Subject Population .......................................................... 98
5.6.4
Selection of Doses in the Study ............................................................ 98
6.0
Complaints........................................................................... 98
6.1
Medical Complaints ............................................................................. 99
6.1.1
Definitions ........................................................................................... 99
6.1.1.1
Adverse Event...................................................................................... 99
6.1.1.2
Serious Adverse Events.......................................................................100
6.1.1.3
Adverse Events of Special Interest.......................................................102
6.1.2
Adverse Event Severity .......................................................................103


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6.1.3
Relationship to Study Drug..................................................................103
6.1.4
Adverse Event Collection Period.........................................................104
6.1.5
Adverse Event Reporting.....................................................................105
6.1.6
Pregnancy............................................................................................107
6.2
Product Complaint...............................................................................107
6.2.1
Definition............................................................................................107
6.2.2
Reporting ............................................................................................108
7.0
Protocol Deviations ........................................................... 108
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 109
8.1
Statistical and Analytical Plans............................................................109
8.1.1
Analysis Datasets ................................................................................109
8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition, and Concomitant Medication ...........................................110
8.1.3
Efficacy Analysis ................................................................................112
8.1.3.1
Primary Efficacy Analysis...................................................................112
8.1.3.2
Secondary Efficacy Analysis ...............................................................114
8.1.4
Safety Analysis....................................................................................115
8.1.4.1
OMT and LCIG Study Drug Exposure ................................................115
8.1.4.2
Adverse Events....................................................................................116
8.1.4.3
Clinical Laboratory Variables..............................................................117
8.1.4.4
Vital Sign Variables and Weight..........................................................117
8.1.4.5
ECG Variables ....................................................................................118
8.1.4.6
Additional Safety Variables.................................................................118
8.1.5
Interim Analysis..................................................................................118
8.2
Determination of Sample Size .............................................................119
8.3
Randomization Methods......................................................................119
9.0
Ethics.................................................................................. 120
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................120
9.2
Ethical Conduct of the Study...............................................................120
9.3
Subject Information and Consent.........................................................121
9.3.1
Informed Consent Form and Explanatory Material ..............................121


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9.3.2
Revision of the Consent Form and Explanatory Material .....................121
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 122
10.1
Source Documents...............................................................................122
10.2
Case Report Forms..............................................................................122
11.0
Data Quality Assurance .................................................... 124
12.0
Use of Information ............................................................ 124
12.1
Subject Privacy....................................................................................124
13.0
Completion of the Study ................................................... 125
14.0
Investigator's Agreement.................................................. 126
15.0
Reference List.................................................................... 127
List of Tables
Table 1.
TEAEs Reported in ≥ 10% of Subjects by Descending Frequency 
(Open-Label LCIG Analysis Set).......................................................... 32
Table 2.
Prohibited Medications and Treatments................................................ 53
Table 3.
Study Activities.................................................................................... 57
Table 4.
Clinical Laboratory Tests ..................................................................... 69
Table 5.
Study Drug........................................................................................... 92
Table 6.
Investigational Devices Provided for Delivery of Drug......................... 92
List of Figures
Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System ............................ 25
Figure 2.
Study Design Schematic....................................................................... 35
Figure 3.
Adverse Event Collection....................................................................105
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................134
Appendix B.
List of Protocol Signatories .................................................................136
Appendix C.
UK Parkinson's Disease Society Brain Bank Clinical Diagnostic 
Criteria................................................................................................137


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Appendix D.
Potentially Clinically Significant Laboratory Values for 
Study M12-927*..................................................................................139
Appendix E.
Protocol Amendment:  List of Changes ...............................................144


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3.0
Introduction
The combination of levodopa-carbidopa continues to be a mainstay in the treatment of 
Parkinson's disease (PD).1-3  As PD progresses, PD patients treated with oral levodopa 
may develop persistent motor fluctuations characterized by unpredictable swings from 
mobility to immobility ("On-Off" phenomenon) or levodopa-induced dyskinesia.  Motor 
fluctuations occur in about 40% of patients after 4 to 6 years of treatment with levodopa 
and up to 90% of patients may experience motor fluctuations after 10 years of levodopa 
therapy.4  The mechanisms by which response fluctuations occur are only partially 
understood but are thought to include presynaptic neuronal degeneration leading to a lack 
of buffering of released levodopa, postsynaptic changes in dopamine receptor sensitivity 
and number, and pharmacokinetic and pharmacodynamic influences of exogenously 
administered dopaminergic agents.5,6  Fluctuations in plasma levels of levodopa occur due 
to the short half-life of levodopa and the unpredictable variability of gastric emptying.  As 
a result, advanced PD patients suffer severe disability due to constant or unpredictable 
motor fluctuations, despite increases in the dose or frequency of their oral levodopa 
treatment.
Various approaches have been taken to cope with the increasingly unstable levodopa 
response.  Levodopa dose and frequency of administration are usually adjusted, although 
many patients find it challenging to take frequent oral doses of medication.  Oral 
formulations of levodopa are often prescribed in combination with long-acting dopamine 
agonists, monoamine oxidase inhibitors (MAO Inhibitors) and catechol O 
methyltransferase (COMT) inhibitors as well as apomorphine injection on an as needed 
basis.  However, despite individually optimized treatment with these conventional 
medications, patients with advanced PD experience inadequate control of their motor 
performance.  A number of more invasive approaches have been explored and utilized 
with varying degrees of success; they include the continuous intravenous (IV) 
administration of levodopa,7-10 and deep brain stimulation (DBS).11  DBS has been used in 
the treatment of advanced PD patients and has demonstrated improvement of motor 
fluctuations in this patient population, but serious and severe adverse events have been 


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reported in approximately 13% – 40% of patients including intracerebral hemorrhage, 
intracranial infection and death.12,13  The procedure is also not available in all settings and 
not all PD patients are candidates for brain surgery.14  Continuous administration of IV 
levodopa is not clinically feasible due to technical limitations.  However, studies with 
constant-rate delivery (infusion) of levodopa to the blood have clearly resulted in marked 
stabilization of motor performance in advanced PD patients.9,10,15
In addition to motor symptoms and motor fluctuations, patients with advanced PD also 
suffer from a constellation of non-motor symptoms (NMS) that is often overlooked yet 
also causes significant disability and impairment to quality of life.  The pathophysiology 
of NMS is poorly understood, but dysfunction of both dopaminergic and 
nondopaminergic systems are implicated in their development.  Non-motor symptoms 
consist of autonomic dysfunction (orthostatic hypotension, constipation, sialorrhea, sexual 
dysfunction, urinary retention, temperature dysregulation, and sweating), cognitive and 
affective disturbances, sleep disorders, and sensory complaints.
Martinez-Martin et al have recently demonstrated that non-motor symptoms have, as a 
whole, a greater impact on health related quality of life (HRQoL) than motor symptoms.16  
Moreover, they have demonstrated that NMS progression contributes importantly to 
HRQoL decline in patients with Parkinson's disease.  Similarly, Hinnell et al 
demonstrated that depression, anxiety, and other non-mood, non-cognitive NMS had a 
greater impact on HRQoL (as measured by the Parkinson's Disease Questionnaire 
[PDQ]-8) than motor symptoms.17  In the PRIAMO study,18 which assessed NMS in over 
1,000 PD subjects using a semi-structured interview questionnaire consisting of 12 NMS 
domains defined by the steering committee, 98.6% of subjects reported the presence of 
NMS.  The prevalence of NMS was evaluated by dividing PD subjects into 3 groups:  
"naïve" subjects who had not been treated with dopaminergic agents, "stable" subjects 
who were under dopaminergic treatment and had no motor complications, and 
"complicated" subjects who had developed motor fluctuations and/or dyskinesia under 
dopaminergic treatment.  The most common NMS and their prevalence in PD subjects 
were as follows:  fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency 


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and nocturia (35%), drooling of saliva, and difficulties in maintaining concentration 
(31%).  The NMS domains of gastrointestinal, pain, urinary, sleep, and skin disorders and 
"miscellaneous" were more frequent in the "stable" and "complicated" subjects than in the 
"naïve" subjects.  However, the frequency of cardiovascular symptoms, fatigue, apathy, 
attention/memory, psychiatric, and respiratory symptoms did not differ across the 
3 groups.  The prevalence of sleep disorders increased with disease severity.  Sleep 
disorders were reported by 47.9% and 81.6% of subjects with mild (Hoehn and Yahr 
stage = 1) and severe (Hoehn and Yahr stage = 4 – 5) disease respectively.  The mean 
number of NMS per subject was 7.8 during the prior month and the frequency of NMS 
increased with disease duration and severity of disease.  Using a structured questionnaire 
of 54 questions on various NMS, Witjas et al found that 64% of PD patients had 
experienced drenching sweats, 44% flushing, 44% oral dryness, and 40% constipation.19   
These symptoms were associated with a high disability rating and poorer quality of life.  
Other prevalent NMS include sleep disturbances (insomnia, daytime sleepiness, restless 
legs and intense vivid dreams), impaired memory and concentration, depression, and 
dribbling.20  PD patients suffer from a variety of sleep disturbances including excessive 
daytime sleepiness, fragmented sleep, REM (rapid eye movement) behavioral sleep 
disorder (RBD), periodic limb movements of sleep (PLMS), restless leg syndrome (RLS), 
sleep apnea and insomnia.  Ondo et al evaluated the prevalence of nocturnal sleep 
disorders in over 300 PD subjects with an average disease duration of 9 years and a mean 
Hoehn and Yahr score of 2.5 using a survey combining questions from various sleep 
scales.21  The study demonstrated that 43% of subjects experienced RBD, 51% 
somniloquism (talking in their sleep), 39% snoring (indicative of sleep apnea), 20% RLS, 
and an average of almost 3 awakenings per night.  Additionally, the PRIAMO study found 
that 64% of PD subjects suffered from sleep disorders overall with 75% in Hoehn and 
Yahr stage 2.5 – 3 and 82% in Hoehn and Yahr stage 4 – 5.18  Non-motor symptoms also 
lead to increased hospitalizations, morbidity, and mortality in PD patients.  Finding
effective treatments for NMS in PD is equally important as treating motor symptoms to 
address significant patient impairment and reduced quality of life.


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Levodopa-Carbidopa Intestinal Gel (LCIG) has been marketed for 10 years.  The LCIG 
System is currently approved in 42 countries for the treatment of levodopa-responsive 
advanced PD.  In the majority of countries, it is marketed under the trade name Duodopa.  
LCIG is a suspension of levodopa-carbidopa monohydrate (4:1) in an aqueous gel 
(carboxymethyl cellulose) with a viscosity that permits homogeneous distribution of 
micronized substance particles.  Upon 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 within the individual's therapeutic window.  When delivered 
via continuous intestinal infusion therapy, LCIG  reduces "Off" time and increases "On" 
time compared to oral levodopa-carbidopa.22  Some studies suggest that the improvement 
of LCIG infusion may be correlated with the severity of Parkinsonian symptoms while on 
oral treatment.23  The delivery of LCIG directly to the upper intestine is anticipated to 
result in the following:2,15
●
Continuous delivery of levodopa-carbidopa
●
Avoidance of the effects of pulsatile gastric emptying
●
Reduced variability in plasma-levodopa concentrations
●
Decreased motor fluctuations and dyskinesia
Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System


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LCIG is delivered to the proximal small intestine through a 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 by an infusion pump as illustrated in Figure 1.  Efficacy of 
upper-intestinal administration of LCIG has been demonstrated in Phase 3 studies.  In the 
pivotal Phase 3 study (Study S187.3.001/Study S187.3.002), compared to 
Levodopa-Carbidopa Immediate Release (LC-IR), LCIG significantly improved "Off" 
time (LS Mean difference = –1.91 hours, P = 0.0015) and "On" time without troublesome 
dyskinesia ("On" time without dyskinesia + "On" time with non-troublesome dyskinesia, 
LS Mean difference = 1.86 hours, P = 0.0059) at Week 12.  At Week 12, compared with 
LC-IR, LCIG significantly decreased the percentage of the waking day in the "Off" state 
and significantly increased the percentage of waking day in the "On" state without 
troublesome dyskinesia.  LCIG also produced a significantly greater change from baseline 
in "On" time without dyskinesia compared to LC-IR.  Most adverse events were transient 
and were mild or moderate in intensity and were generally associated with the PEG-J 
procedure and its complications.  The most common adverse events were complication of 
device insertion (56.8%), abdominal pain (51.4%), nausea (29.7%), procedural pain 
(29.7%), constipation (21.6%) and incision site erythema (18.9%).16
Improvements were also seen with LCIG in disease-specific and global Quality of Life 
(QoL) measures, as assessed by Clinical Global Impression-Improvement scale (CGI-I), 
Parkinson's Disease Questionnaire-39 Item (PDQ-39) total scores, and EuroQol Visual 
Analogue Scale (EQ VAS) scores.24
In a long-term open-label safety study (Study S187-3-004) conducted over 54 weeks with 
324 subjects, a clinically meaningful reduction in "Off" time was apparent by Week 4 and 
persisted to the Week 54 endpoint.  All of the reduction in "Off" time (4.44 hours, 
P < 0.001) was accompanied by an increase in "On" time without troublesome dyskinesia 
(4.80 hours, P < 0.001), as was observed in the pivotal study.  This improvement was 
achieved with the majority of subjects (> 75%) requiring only levodopa-carbidopa therapy 
for treating their PD symptoms throughout the study.  The most common adverse events 


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(≥10% of subjects) were complication of device insertion (34.9%), abdominal pain 
(31.2%), procedural pain (20.7%), nausea (16.7%), excessive granulation tissue (16.0%), 
postoperative wound infection (15.4%), fall (15.1%), constipation (14.5%), insomnia, 
(13.6%), incision site erythema (13.0%), and urinary tract infection (11.4%).  For each of 
these preferred terms, the adverse events for the majority of subjects were mild to 
moderate as assessed by the investigator.
Just as LCIG is effective in treating motor fluctuation in advanced PD, it has the potential 
to treat many of the NMS associated with PD as well.  Typically, treatment of any of these 
NMS require additive therapy and exposes the patient to drug-drug interactions as well as 
the potential side effect from these therapies.  Non-motor symptoms can be present early 
in the course of the disease and even predate motor symptoms, but remain present in all 
stages of the disease and become more prominent as the disease progresses.18  These 
symptoms can be more troublesome than the cardinal parkinsonian motor symptoms and 
contribute to significant disability, and to the worsening of quality of life of both patients 
and caregivers.16,24
Although NMS have been implicated in PD since the original description by James 
Parkinson in 1817, only recently have they been well recognized as important features of 
the disease.26  There are 2 primary reasons why NMS has not been recognized as 
important features of disease:  1) Lack of disease specific instruments to assess NMS and 
2) Treatments for PD typically focus on control of motor symptoms; consequently, NMS 
tend to be underreported and inadequately treated in the clinical setting.27,28  One study in 
the US demonstrated that existing depression, anxiety and fatigue are not identified by 
neurologists in over 50% of consultations, and existing sleep disturbances in over 40%.29  
To date, there have been a few small investigator initiated studies assessing the effect of 
LCIG on NMS.  In a pilot study by Honig et al switching from oral medications to 
continuous infusion of LCIG reduced motor complications in advanced PD, as well as the 
burden of NMS.30  In this prospective open-label observational study, 22 advanced PD 
patients (mean age 58.6 years, duration of disease 15.3 years) were followed for 6 months 
and the effect of LCIG on NMS was assessed by the NMSS, Parkinson's disease sleep 


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scale (PDSS) and PDQ-8.  A statistically significant beneficial effect was shown in the 
NMSS total score (56% improvement from baseline) and 6 of the 9 domains of the 
NMSS:  cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and 
miscellaneous (including pain and dribbling).  These results paralleled the improvement 
observed in motor symptoms.  In addition, significant improvements were found on the 
PDSS (33% improvement from baseline) and in health-related quality of life (assessed by 
the PDQ-8).  The improvement in PDQ-8 scores was significantly correlated with changes 
in NMSS scores.
Reddy et al compared the effect of LCIG on NMS in 17 advanced PD subjects treated 
with LCIG versus 9 matched PD controls not treated with LCIG over 6 months.31  There 
were no significant changes in NMS as measured by the Non-Motor Symptoms Scale 
(NMSS) in the control group while the LCIG treated subjects demonstrated a significant 
improvement in NMSS total score (P = 0.004) and the subdomains of sleep, 
gastrointestinal, urinary, and sexual function.  The differences in change from baseline to 
follow-up between the Duodopa treated group and the control group was statistically 
significant for NMSS total score (P = < 0.027) and for the subdomains of cardiovascular, 
sleep, gastrointestinal, urinary, sexual function, and miscellaneous.
Pusuiainen et al examined the effects of LCIG on NMS in 9 PD subjects over 
two months.32  Statistically significant improvement was seen in the NMSS total score 
(52% decrease, P = 0.008) and the subdomains of sleep/fatigue, gastrointestinal, and 
miscellaneous.
A retrospective study that evaluated change from baseline in NMS using the NMSS 
instrument in 14 subjects with advanced PD treated with LCIG for an average of 
25 months also demonstrated 14% improvement in the NMSS total score but the results 
did not reach statistical significance.30  Although some of the individual domains showed 
improvement with LCIG, none reached statistical significance.  Psychiatric symptoms 
were significantly improved as revealed by a significant reduction in Unified Parkinson's 
Disease Rating Scale (UPDRS) Part I, Neuropsychiatric Inventory, and Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson's Disease.  Additionally, an improvement 


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in sleep quality and diurnal somnolence was demonstrated by the significant reduction of 
the PDSS.
When specifically evaluating the effect of LCIG on sleep in Parkinson's disease patients, 
no previous studies have compared LCIG to optimized medical therapy using the PDSS-2 
as an endpoint.  Results from a prospective baseline control study conducted by Zibetti 
et al showed that the improvement in PDSS-2 total score was 13.1 (34% improvement) 
after an average of 3.5 months of LCIG treatment.33
Until recently, NMS were thought to be resistant to dopaminergic therapy.  However, 
dopaminergic agents have now been shown to improve depression, REM behavioral sleep 
disorder, nocturia, and erectile dysfunction.34  Dopaminergic agents can also improve 
"Off"-related NMS, such as pain, anxiety, flushing, and depression.  Although it is 
becoming more recognized that dopaminergic agents can treat certain NMS, their 
supposed effectiveness was limited by the lack of scales to assess NMS, and quantify their 
impact on a patient's overall wellbeing.  Motor and non-motor symptoms closely correlate 
with fluctuating plasma concentrations of levodopa and the corresponding pulsatile 
concentration of dopamine in the striatum.35-37  Plasma levels of orally administered 
levodopa fluctuate significantly due to its short half-life and the variability in gastric 
emptying.38,39  Treatments that offer continuous levodopa administration result in less 
variability in levodopa plasma concentration and are believed to provide more continuous 
dopaminergic stimulation, and, therefore, reduce the frequency and severity of motor 
fluctuations, dyskinesia, and non-motor symptoms.40,41  Therefore, reducing the amount of 
"Off" time should improve those fluctuating NMS.  Additionally, since LCIG is initiated 
and often maintained as monotherapy, tapering off of other anti-PD medications may also 
lead to improvement in certain non-motor symptoms.  Continuous delivery of levodopa, 
which has the potential to offer continuous dopaminergic stimulation has potential to lead 
to neuroplastic changes that may also improve those non-fluctuating NMS. 
An understanding of LCIG effects on NMS can provide important information for 
physicians, patients and caregivers when assessing the benefits of advanced treatment.


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3.1
Differences Statement
In previous Phase 3 LCIG studies as part of the US registration package which studied 
adult subjects with advanced levodopa-responsive PD with persistent motor-fluctuations 
despite optimized treatment with available PD medications, the primary efficacy endpoint 
was change in motor fluctuations (specifically "Off" time).  Study M12-920, an ongoing 
Phase 3b open-label single arm, baseline-controlled study, with an out-patient PEG-J 
procedure, evaluated the effect of LCIG on non-motor symptoms in advanced PD in 
36 subjects using the NMSS; however effect of LCIG on sleep using the PDSS-2 is not 
being evaluated.  This study will be the largest, randomized, parallel group study 
evaluating the effect of LCIG on NMS compared to optimized medical therapy as
assessed by both the NMSS and PDSS-2.
3.2
Benefits and Risks
Benefits
LCIG provides continuous rather than intermittent stimulation of the dopaminergic 
receptors in the brain by maintaining constant plasma concentrations of levodopa.  The 
gel formulation, typically applied in a monotherapy regimen, allows a greater flexibility in 
individualized dosing, thereby allowing the plasma concentration to be within the narrow 
therapeutic window of these advanced PD patients.
Efficacy of LCIG on motor symptoms in subjects with advanced PD has been 
demonstrated in Phase 3 studies.  In the pivotal Phase 3 study (3.001/3.002), compared to 
LC-IR, LCIG significantly improved "Off" time (LS Mean difference = –1.91 hours) and 
"On" time without troublesome dyskinesia (LS Mean difference = 1.86 hours) at 
Week 12.  LCIG also demonstrated a statistically and clinically significant impact on 
subject's quality of life as assessed with the PDQ-39 summary index and the UPDRS 
Part II score.  Subjects with advanced Parkinson's disease who qualify for the study are 
expected to benefit through better control of the motor fluctuations that are not adequately 
controlled with PD medications.17  Additionally, as described above, small studies have 


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demonstrated improvement in NMSS total score, NMSS subdomains and PDSS-2 with 
LCIG either versus optimized medical therapy or in open-label, single-group studies.  
Risks
Due to the long experience with the oral drug combination of levodopa and carbidopa for 
the treatment of PD, the risks that are associated with both active pharmaceutical 
ingredients are well known.  These and additional information on risks are available in the 
Investigator's Brochure.42
Adverse events of special interest (AESI) related to LCIG, a therapeutic system consisting 
of the drug, the devices, and the placement procedure for  the NJ or PEG-J tubing,  have 
been identified and form the basis of the European Union Risk Management Plan.43  
AESIs for this study are defined in Section 6.1.1.3 and comprise the following:
Known Risks
●
Gastrointestinal and Gastrointestinal Procedure Related Events
Potential Risks
●
Polyneuropathy
●
Weight Loss
In the previous Phase 3 clinical program, as observed in an integrated summary of safety, 
AEs were common and occurred in 93.9% of the 412 subjects in the Open-Label LCIG 
Analysis Set (Phase 3 Studies S187.3.003, S187.3.004, and S187.3.005).  The most 
common treatment emergent adverse events (TEAEs) were complication of device 
insertion (33.3%), abdominal pain (28.2%), postoperative wound infection (23.5%), 
insomnia (23.3%), fall (23.1%), procedural pain (20.9%), excessive granulation tissue 
(20.6%), nausea (20.4%), constipation (20.4%), and incision site erythema (20.1%) 
(Table 1).  These AEs are commonly associated with underlying PD or are frequently 
observed following PEG-J placement.  Treatment emergent adverse events reported in 
≥10% of subjects by descending frequency in a pooled open-label analysis set 


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representing a mean treatment duration of 854 days (open-label LCIG analysis set) are in 
Table 1.
Table 1.
TEAEs Reported in ≥ 10% of Subjects by Descending Frequency 
(Open-Label LCIG Analysis Set)
Preferred Term
N = 412
Number (%) of Subjects
Any adverse event
387 (93.9)
Complication of device insertion
137 (33.3)
Abdominal pain
116 (28.2)
Postoperative wound infection
97 (23.5)
Insomnia
96 (23.3)
Fall
95 (23.1)
Procedural pain
86 (20.9)
Excessive granulation tissue
85 (20.6)
Nausea
84 (20.4)
Constipation
84 (20.4)
Incision site erythema
83 (20.1)
Urinary tract infection
71 (17.2)
Vitamin B6 decreased
65 (15.8)
Anxiety
61 (14.8)
Procedural site reaction
61 (14.8)
Dyskinesia
60 (14.6)
Parkinson's disease
59 (14.3)
Weight decreased
59 (14.3)
Depression
55 (13.3)
Blood homocysteine increased
56 (13.6)
Back pain
46 (11.2)
Post procedural discharge
45 (10.9)
Orthostatic hypotension
44 (10.7)
Vomiting
43 (10.4)
Diarrhoea
43 (10.4)
Headache
41 (10.0)


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SAEs occurred in 47.1% of the 412 subjects in a pooled Open-Label LCIG Analysis Set 
(Phase 3 Studies S187.3.003, S187.3.004, and S187.3.005).  SAEs that occurred in ≥ 2% 
of subjects were as follows:  Complications of device insertion (7.8%), pneumonia 
(4.9%), abdominal pain (4.1%), hip fracture (2.4%), Parkinson's disease (2.4%), 
peritonitis (2.4%), weight decreased (2.4%), fall (2.4%), polyneuropathy (2.2%) and 
device dislocation (2.2%).  These data are on file at AbbVie.
4.0
Study Objective
Primary Objective:
The primary objective of this study is to examine the effect of LCIG relative to that of 
OMT on NMS associated with advanced PD as assessed by the NMSS Total Score and 
the Modified PDSS-2 Total Score. 
Secondary Objectives:
To assess the effect of LCIG relative to that of OMT on the motor symptoms/motor 
complications, safety, tolerability and health-related outcome measures.
Motor symptoms/motor complications will be measured by:
●
UPDRS Parts III and IV
Safety and tolerability will be assessed by:
●
Adverse event monitoring
●
Neurological exams
●
Clinical laboratory evaluations
●
Electrocardiogram
●
Vital signs and weight
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Minnesota Impulsive Disorders Interview (MIDI)
●
Sleep Attacks Questionnaire (SAQ)


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Health Related Outcomes will be measured by:
●
Parkinson's Disease Questionaire-8 (PDQ-8)
●
Clinical Global Impression of Change (CGI-C)
●
UPDRS Parts I and II
●
Patient Global Impression of Change (PGIC)
●
Parkinson Anxiety Scale (PAS)
●
Geriatric Depression Scale (GDS-15)
●
King's PD Pain Scale
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, multicenter 26-week study comparing LCIG to OMT on 
NMS associated with advanced PD.  This study will be conducted at approximately 40 –
50 sites that specialize in movement disorders in approximately 10 countries.


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Figure 2.
Study Design Schematic
The study is designed to enroll an adequate number of subjects such that approximately 
88 subjects will be randomized in a 1:1 ratio to either treatment group of OMT or LCIG in 
order to meet scientific and regulatory objectives without over-enrolling an undue number 
of subjects in alignment with ethical considerations.
The study will consist of 3 sequential periods:  Screening, Treatment and Follow-Up.
5.1.1
Screening Period
The Screening Period visits will be the same for all subjects screened into the study.  The 
Screening Period will consist of three visits, Visit 1 (V1), Visit 2 ([V2] [optional]) and the 
Randomization Visit (V3) in which the subject will be assessed to determine eligibility.  
A movement disorder specialist should perform a screening interview of the subject.  The 
duration of the Screening Period can be between 30 – 67 days to accommodate the 
required procedures, training and collection of diaries, and allow for stabilization of 


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anti-PD medications and medications to treat NMS.  A stable regimen is defined as no 
changes to the frequency of administration, dose of administration or total daily dose.  
During the Screening Period, no study drug will be administered.
Visit 1 (V1)
Following informed consent, at V1, study eligibility will be assessed through a series of 
tests and scales.  V1 assessments may be performed over a period of multiple days.  Refer 
to Table 3 of Section 5.3.1.1 for a detailed list of assessments and procedures.  
●
Laboratory results should be available before V3 (or optional V2) to review for 
continued subject eligibility. 
●
The UPDRS, Part III, will be completed during the subject's "Off" and best 
"On" times.  The practically defined "Off" time UPDRS will be done in the 
morning prior to the subject taking their first daily dose of anti-PD medication.  
At a minimum a subject should be 8 hours without anti-PD medication before 
the UPDRS is completed.  The best "On" time rating will usually be done 1 to 
2 hours post any morning dose of study drug or anti-PD medications but prior 
to lunch.  If possible, the UPDRS should be done at the same time of day 
throughout the trial.  The "Off" time UPDRS will only be done during 
Screening; all other UPDRS assessments will be done during "On" time.
●
The PI should discuss with the subject the placement of an NJ and/or PEG-J 
and a decision made at this time if they will do the optional NJ period or go 
directly to PEG-J should they be randomized to the LCIG treatment group.  
This is to allow for scheduling of the NJ and/or PEG-J at this time.
●
The time period between V1 and optional V2 should not exceed 60 days.
●
Additionally, a GI exam to determine suitability for PEG-J placement and a 
dermatologic evaluation for the presence of melanoma must be performed 
prior to V3 (or optional V2).
●
All anti-PD medications and medications to treat NMS must be stable for at 
least 30 days prior to V3.


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Optional Visit 2 (V2)
Visit 2 will occur between 30 to 60 days after V1.  Visit 2 is optional and is based on the 
Investigator's discretion of individual subject need during stabilization of anti-PD 
medications and medications to treat NMS.  Subjects must be on stable anti-PD 
medications and medications to treat NMS for at least 30 days before V2.  However, the 
time period between V1 and V2 must not exceed 60 days.  If, in the PIs opinion, it is 
medically necessary for the time frame between V1 and V2 to exceed 60 days, the PI 
should discuss this with the medical monitor.
All anti-PD medications and medications to treat NMS must remain stable between V2 
and V3.
Visit 3 (V3)
Visit 3 will be the randomization visit.  The timeframe from V2 to the V3 will be
3 – 7 days. 
Only those subjects who meet the following randomization criterion will be randomized at 
the end of V3 to one of the treatment groups:
●
Subject must have a minimum PDSS-2 total score of 18 at Baseline 
assessment.
In addition at V3 the following should occur:
●
Concomitant Medication (including anti-PD medications); Subjects' anti-PD 
medications must be stable during the 3 – 7 days between V2 and V3.
●
Anti-PD Medication History:  NMS Medication History:  medications used to 
treat individual non-motor symptoms (e.g., Insomnia, depression, anxiety).  
Subjects' medications to treat NMS must be stable during the 3 – 7 days 
between V2 and V3.
●
Training on the LCIG System and Pump will be initiated only for subjects 
randomized for LCIG and their caregivers, as applicable.


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●
UPDRS, Parts I – V will be completed during the subject's "On" time.
5.1.2
The Treatment Period
5.1.2.1
OMT Group
Those subjects randomized to OMT at the end of V3 will continue on their current 
anti-PD medication regimen for the duration of the study.  The PI will provide the 
prescription for continued OMT.  PIs should make any effort to keep all anti-PD 
medications and medications to treat NMS stable for the duration of the study.  Changes 
to the OMT arm can be made "if medically justified" or if absolutely indicated for safety 
reasons.  The day after V3 will be considered Day 1 of the treatment period for the OMT 
group.  Subjects in the OMT Group will not have a Visit 4, while visits 5 through 8 will 
take place at the end of Weeks 2 through 26 respectively.  Data from all visits will be 
recorded on the appropriate eCRF and the assessments completed as in Table 3.
5.1.2.2
LCIG Treatment Group
Tapering of Anti-PD Medications Other Than Levodopa
All subjects randomized to the LCIG group should have all anti-PD medications, with the 
exception of levodopa formulations, tapered off within 14 days after randomization 
according to the prescribing information and the discretion of the Investigator.  All other 
antiparkinsonian medication, including dopamine-agonists, apomorphine, 
COMT-inhibitors, selective MAO-B inhibitors, amantadine, etc., must be discontinued 
prior to LCIG initiation.  All anti-PD medications, other than subcutaneous continuous 
delivery of apomorphine and levodopa formulations as outlined in the allowable 
medications section can be restarted 28 days after LCIG initiation if medically necessary 
for the treatment of Parkinsonian symptoms.
NJ and/or PEG-J Placement
LCIG is intended for continuous intestinal administration.  A temporary NJ tube may be 
used initially with the infusion pump to determine if the subject responds favorably to this 


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method of treatment and to optimize the dose of LCIG before treatment with a permanent 
percutaneous endoscopic gastrostomy with a jejunal (PEG-J) tube is started.  
Alternatively, subjects may proceed directly to placement of the permanent PEG-J tube 
and perform titration without the NJ phase if deemed appropriate by the Investigator. 
Visit 4 (V4), Day 1 Optional Nasojejunal (NJ) Phase and/or PEG-J Placement
Subjects will have the NJ and/or PEG-J tube placement procedure performed on Study 
Day 1 by a gastroenterologist proceduralist or qualified radiologist (or delegated 
experienced nurse for NJ).  V4 assessments must be performed on the same day that the 
NJ and/or PEG-J tube is placed with the following exception:  if NJ is used and placed via 
the passive method, the radiological check will be completed when the tube is expected to 
be located in the correct position (which may take around 48 hours and local practice 
procedures should be followed).  The NJ and/or PEG-J tube will be placed such that the 
end of the tubing is just beyond the ligament of Treitz.  Once there is confirmation of tube 
placement all necessary procedures will be followed to attach the pump, with the LCIG 
cassette, to the NJ and/or PEG-J tube to initiate treatment with LCIG.  The 
gastroenterologist proceduralist or surgeon will check the subject's stoma site within 
24 hours of the PEG-J placement. 
The optional NJ Period will end with the decision to either continue with treatment and 
the placement of a permanent jejunal extension tube by PEG-J placement procedure or to 
discontinue further treatment.  
Certain procedures will be repeated prior to PEG-J placement for those who underwent 
the NJ period as outlined in the table of activities (Table 3).  The NJ tube will be removed 
at the time of the PEG-J procedure, or upon discontinuation of treatment with LCIG.  If 
the subject does not enter the PEG-J placement procedure phase of the study, all 
End-of-Study Treatment assessments, defined for Visit 9, Week 27, should be completed.


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LCIG Initiation and Titration
Following optional NJ and/or PEG-J placement on Study Day 1 and, at the discretion of 
the Investigator, the subject may begin initiation and titration of LCIG infusion on Study 
Day 1 once tube placement is confirmed.  All other oral anti-PD medications must be 
stopped prior to LCIG initiation.  The dose of LCIG should be adjusted to obtain the 
optimal clinical response for the individual subject.  Optimal clinical response, or 
optimization, is defined as maximizing the functional "On" time during the day and 
minimizing the number of "Off" episodes (bradykinesia) and the time the subject is "Off."  
In addition, optimization minimizes "On" time with troublesome dyskinesia.  This 
determination is made by the Investigator.  The dosage procedures for LCIG are described 
in Section 5.5.1 Treatments Administered.  
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a 
tool to achieve dose optimization.  In the event it is used it should be completed hourly 
until the dose is optimized and then once AM and once PM it will be completed until the 
subject is discharged. 
Oral levodopa medication may only be used as a supplement during the night following 
discontinuation of the LCIG infusion.  During the day it should be used ONLY as rescue 
medication in case of acute deterioration, presumably caused by failure of the tubes and/or 
the pump or the onset of an acute illness.
It may take several days to optimize LCIG treatment.  In some subjects, optimization may 
take longer and subjects may remain hospitalized at the discretion of the Investigator.  For 
those subjects with an NJ placement they may or may not continue the NJ Period at home 
until the PEG-J is inserted.
During the initial titration phase, extra doses may be administered by the Investigator or 
subject every hour.  Pump programming should only be done by trained site personnel 
and all dose changes must be approved by the Investigator.  After the nightly 
discontinuation of LCIG drug administration, levodopa-DDI (DOPA decarboxylase 


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inhibitor) tablets may be taken up to 2 hours (for oral LC-IR) or 4 hours (for oral LC-CR) 
prior to the administration of the next morning dose of LCIG and should not be counted as 
rescue.  While the subject is in the hospital, the study staff may use the Dose Titration 
Diary as a tool to achieve dose optimization.  In the event it is used it should be completed 
hourly until the dose is optimized and then once AM and once PM it will be completed 
until the subject is discharged.  All adjustments can be recorded on the Dose Titration 
Diary allowing the Investigator to appropriately adjust, if needed, the following day's 
morning dose, continuous infusion rate and extra dose until the subject is optimized.  It is 
up to the discretion of the Investigator to determine how many titration days are necessary 
to obtain optimal clinical response.  Once optimized, dose adjustments to LCIG can be 
made up to Day 28.  After Day 28 the dose should remain stable for the duration of the 
study unless adjustments are absolutely needed for safety reasons.
During the titration, the subject (and if applicable, their care-partner) will receive 
refresher training on stoma care, tube care and the use of the pump, as well as all the 
necessary procedures for device maintenance and documentation of LCIG cassette use.
Titration can be done as an inpatient or outpatient.  In the event the subject is no longer 
hospitalized but still being titrated to LCIG the subject will visit the site or clinic as 
needed for treatment optimization.  These visits will be recorded on the appropriate eCRF 
and the assessments completed as in Table 3.
The gastroenterologist proceduralist or surgeon will check the subject's stoma site anytime 
from Day 2 to 7 after the PEG-J procedure.
Treatment:  Visit 5 (Week 2) Initial Post-PEG-J Evaluation Through Visit 8 
(Week 26)
Visit 5 will be conducted at Week 2, 14 days post NJ and/or PEG-J insertion.  If subjects 
are hospitalized for the full 14 days of the NJ and/or PEG-J Placement Procedure Period 
this visit will take place when the subject is still in the hospital.  If subjects have been 
discharged prior to V5, it will be conducted as a site visit.  Study activities at V5 (Week 2) 
must be completed even if the subject titration is still occurring.  Visits 6, 7 and 8 at the 


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end of Weeks 6, 12 and 26 respectively will be recorded on the appropriate eCRF and the 
assessments completed as in Table 3.
Allowed anti-PD medications (as indicated in Section 5.2.3.2) may be restarted or 
initiated if indicated by the condition of the subject, but not within 28 days after PEG 
placement procedure.  
Drug Dispensing Visits
Subjects and/or caregivers must come into the clinic or pharmacy between V7 (Week 12) 
and V8 (Week 26) for clinical LCIG return and supply visits so that there is no risk of
medication expiring.  The drug dispensing visits will occur at Weeks 17 and 22 
(± 7 days).  Other assessments may be completed during these visits if required.
5.1.3
Study Follow-Up
Follow-Up Visit (V9) (LCIG Subjects not Continuing on Commercial Product)
For subjects who are not continuing on LCIG (through commercial sources in countries 
where LCIG is approved and marketed), the PEG-J tube will be removed following the 
End of Study activities.  A follow-up clinic visit will occur approximately one week later.
Commercial Transition Visits (LCIG Subjects Continuing on Commercial Product)
Study subjects in the LCIG group who complete participation in the study and for whom 
continuation of treatment with LCIG is judged appropriate by the Investigator will 
continue to receive LCIG until transition to commercial product is coordinated with the 
Sponsor's commercial affiliate.
Additional visits every 12 weeks from Week 26 will be schedule to monitor subject safety 
and allow for drug resupply until the subject transfer to commercial LCIG.  Refer to 
Table 3 of Section 5.3.1.1 for list of assessments.  Drug resupply visits will also occur at 
6 week intervals between the every 12 week safety assessments.


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Upon transfer of subjects to commercial LCIG the monitoring of such therapy will be the 
responsibility of the subject's personal physician.  All necessary support will be provided 
by the Sponsor's local representative.  Follow-up care in these circumstances will be based 
on the judgment of the subject's personal physician and no formal collection of data will 
be conducted except for regular ADR-reporting in accordance with local instructions.
OMT Subjects
Study subjects in the OMT group who complete participation in the study are eligible to 
transition to commercial LCIG after end of study procedures if judged appropriate by their 
personal physician.  This transition is not study related.  
5.2
Selection of Study Population
A careful evaluation of any significant change(s) in the subject's PD symptomatology 
during the Screening Period should be performed by the Investigator prior to 
randomization to ensure that the subject still meets Inclusion/Exclusion criteria.  Subjects 
who successfully complete all screening and baseline visits procedures and who satisfy all 
of the Inclusion Criteria and do not meet any of the Exclusion Criteria are eligible for 
randomization.
5.2.1
Inclusion Criteria
Subjects must meet the following criteria in order to participate in this study.
1.
Subject must have a diagnosis of idiopathic Parkinson's disease according to the 
United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria.  See 
Appendix C for UKPDS. 
2.
Subject demonstrates persistent motor fluctuations in spite of individually 
optimized treatment.
3.
The subject's Parkinson's disease is levodopa-responsive.
4.
Subject has had optimized treatment with available anti-PD medication and their 
motor symptoms are judged inadequately controlled on this optimized treatment.  


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Optimized treatment is defined as the maximum therapeutic effect obtained with 
pharmacological antiparkinsonian therapies when no further improvement is 
expected regardless of any additional manipulations of levodopa and/or other 
antiparkinsonian medication.  This will be based on the Investigator's clinical 
judgment.
5.
Subject and/or if applicable, their care-partner must be able to complete the Subject 
Dosing Diary and must be able to demonstrate the ability to operate, manipulate 
and care for the infusion pump and tubing.
6.
Subject is eligible to transfer to commercial treatment of Duodopa after completing 
the study based on local country requirements.
7.
Subject must have a minimum PDSS-2 total score of 18 at Baseline assessment.*
8.
Subject must be able to understand the nature of the study and has had the 
opportunity to have any questions answered.  Prior to the conduct of any study 
procedures (including any changes occurring in the subject's current therapeutic 
regimen), the subject, if judged by the PI to have decision-making capacity, must 
have voluntarily signed the Independent Ethics Committees/Institutional Review 
Board (IEC/IRB) approved Informed Consent.  In the absence of subject's ability to 
provide the informed consent, the informed consent must have been signed by a 
person who has the legal right to act on behalf of the subject following national 
laws.
9.
Male or female subjects at least 30 years of age.
If female, subject must be either postmenopausal defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR


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●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
●
a Woman of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.3.5), starting at Study Day 1 
through at least 30 days after the last dose of study drug.
If the male subject is sexually active, he must agree, from Study Day 1 through at 
least 4 weeks after the last dose of study drug, to practice the protocol specified 
contraception (Section 5.2.3.5).
10.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at Study Day 1.
11.
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy testing.
*
If initially excluded based on this inclusion criterion (from Amendment 2), subject is 
eligible to re-screen.
Rationale for Inclusion Criteria
1 – 7
To select the adequate subject population with appropriate disease severity
8
In accordance with harmonized GCP
9
For the safety of the study subjects
10 – 12
The impact of LCIG on pregnancies is unknown
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Subject's PD diagnosis is unclear or there is a suspicion that the subject has a 
parkinsonian syndrome such as secondary parkinsonism (e.g., caused by drugs, 


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toxins, infectious agents, vascular disease, trauma, brain neoplasm), parkinson-plus 
syndrome (e.g., Multiple System Atrophy, Progressive supranuclear Palsy, Diffuse 
Lewy Body disease) or other neurodegenerative disease that might mimic the 
symptoms of PD.
2.
Subject has undergone neurosurgery for the treatment of Parkinson's disease.
3.
Subject has discontinued apomorphine continuous infusion for the treatment of 
Parkinson's disease less than 3 months prior to screening visit.
4.
Subject has any neurological deficit that might interfere with the study assessments 
(e.g., hemiparesis).
5.
Known hypersensitivity to levodopa, carbidopa or radiopaque material.
6.
Subject has contraindications to levodopa, (e.g., narrow angle glaucoma, malignant 
melanoma).
7.
Subject experiencing clinically significant sleep attacks or clinically significant 
impulsive behavior (e.g., pathological gambling, hypersexuality) at any point 
during the three months prior to the Screening evaluation as judged by the 
Investigator.
8.
Current diagnosis or history of drug or alcohol abuse (DSM-V-TR criteria) within 
12 months prior to screening visit.
9.
Current primary psychiatric diagnosis of uncontrolled acute psychotic disorder or 
primary psychiatric diagnoses of bipolar disorder, schizophrenia, obsessive 
compulsive disorder or currently experiencing a major depressive episode with 
psychotic features per Diagnostic and Statistical Manual of Mental Disorders Fifth 
Edition, Text Revision (DSM-V-TR).
10.
Currently experiencing or any known history of psychosis (e.g., troublesome 
hallucinations with or without insight) or delusions within 3 months prior to 
Screening.


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11.
A Mini-Mental State Examination (MMSE) score of < 24 or significant cognitive 
impairment that, in the opinion of the Investigator, could impact the subject's 
ability to participate in the trial.
12.
Serum glutamic-oxaloacetic transaminase (AST) or serum glutamic-pyruvic 
transaminase (ALT) 3 × the upper limit of normal (ULN), or any abnormal 
laboratory value that is considered clinically significant by the Investigator or could 
interfere with safety assessments.
13.
Current evidence of clinically significant hematological, autoimmune, endocrine, 
cardiovascular, renal or gastrointestinal disorder that would possibly interfere with
the subject's participation in the study (e.g., treated and controlled stable 
hypertension would not be considered an Exclusion).
14.
Subject has current or a history of gastrointestinal, liver, kidney or other condition 
which may interfere with the absorption, distribution, metabolism or excretion of 
the study drug (e.g., gastric or intestinal surgery).
15.
Any malignant disease other than carcinoma in situ of the cervix or basal cell 
carcinoma of the skin within the past five years prior to Screening.  Subjects with 
prostate cancer or completely excised squamous cell carcinoma of the skin without 
reoccurrence within two years prior to Screening may be permitted to enroll 
following Investigator and study designated physician discussion and 
documentation of approval.  No history of antineoplastic and immunosuppressants 
administered for cancer treatment (within last 5 years).  Note:  Biopsy and 
diagnosis must be completed for any suspicious lesion at dermatology or physical 
exam.
16.
A planned surgical procedure scheduled when the subject would be participating in 
this study.  Subject may subsequently be considered for the study following full 
recuperation from the surgical procedure.
17.
Exposure to any investigational drug within 30 days prior to Screening.


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18.
Previous enrollment in this study, any other LCIG study or any prior exposure to 
LCIG.
19.
Current enrollment in another clinical study.
20.
Subject for whom the placement of a PEG-J tube for LCIG treatment is 
contraindicated or is considered a high risk for the PEG-J procedure according to 
the gastroenterology evaluation.
21.
Subject has significant current suicidal ideation within one year prior to Screening 
as evidenced by answering "yes" to questions 4 or 5 on the suicidal ideation portion 
of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at Screening 
or a history of suicidal attempts within the last 2 years.
22.
A low B12 level or low-normal B12 level (less than 300 pg/mL) with elevated 
methylmalonic acid (MMA), at Screening Visit 1.*
23.
Positive screen for drugs of abuse or medical marijuana, at Screening Visit 1.
24.
Consideration by the investigator, for any reason, that the subject is an unsuitable 
candidate to receive LCIG.
25.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 30 days after the last dose of study drug.
26.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 30 days after the last dose of study drug.
*
If treated and repeat labs confirm levels rise above 300 pg/mL, subject is eligible to 
re-screen.
Rationale for Exclusion Criteria
1, 6, 12 – 15, 22, 23
To reduce the risk to subjects or others and/or to exclude 
underlying conditions that would compromise the ability to 
make causality assessments relative to LCIG for safety 
events


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2, 4 – 5, 7 – 11, 16, 20, 
21
To ensure safety of the subjects throughout the study
3, 17 – 19, 24
To exclude, or to minimize, the number of medications or 
other factors that could interfere with the LCIG, or could 
add unnecessary variance or bias to safety evaluations
25 – 26
The impact of LCIG on pregnancies and lactation is 
unknown
5.2.3
Prior and Concomitant Therapy
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).
5.2.3.1
Prior Therapy (Prior to Randomization)
All medications taken by the subject during the study from 30 days prior to signing the 
Informed Consent Form are to be recorded in the eCRF.
5.2.3.2
Concomitant Therapy
All changes to concomitant medications must be carefully documented on the 
Concomitant Medication eCRF form.
Allowable Medications
Anti-Parkinsonian Medications
The following classes of anti-Parkinsonian medications will be allowed during the study:
1.
Levodopa formulations
●
For the OMT group, all levodopa formulations are allowed
●
For the LCIG group:
○
levodopa formulations can only be used at nighttime (the 8 hours when the 
pump is not in use) or as rescue medication


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●
long-acting levodopa formulations can only be used at nighttime (at 
least 4 hours prior the next day's morning dose)
●
short-acting levodopa formulations with the exception of formulations 
containing entacapone can only be used at nighttime (at least 2 hours 
prior to the next day's morning dose) or as rescue medication
2.
Dopamine agonists (not including apomorphine continuous infusion or PRN 
injection)
3.
MAO-B inhibitors
4.
Anti-cholinergics
5.
Amantadine
General Requirements
Screening to Visit 3:  All anti-Parkinson's disease medications must be stable* for at least 
30 days prior to V3 baseline assessments (NMSS and PDSS-2).
*
A stable regimen is defined as no changes to the frequency of administration, dose of 
administration or total daily dose.
Randomization to End of Treatment Period:
●
OMT Group:  all anti-PD medications should remain stable from 
randomization to the Week 26 visit and study assessments. Changes to the 
OMT arm can be made "if medically justified."
●
LCIG Group:  all anti-PD medications except levodopa formulations must be 
tapered off after randomization and prior to LCIG initiation via NJ or PEG-J 
(in those going directly to PEG-J). Time of inverse titration should be done 
following the prescribing information and the Investigator's discretion, but 
should not exceed 14 days after randomization.  For those randomized to 
LCIG, all allowable anti-PD medications listed above can be restarted 28 days 
after LCIG initiation if medically necessary for the treatment of Parkinsonian 
symptoms.


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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, except for study drug for subjects randomized to LCIG.  All changes to 
concomitant medications, this includes all medications taken by subjects randomized to 
OMT, must be carefully documented on the Concomitant Medication eCRF form.
Medications to Treat Non-Motor Symptoms (OMT and LCIG Groups)
Medications used for the treatment of non-motor symptoms (e.g., orthostatic hypotension, 
sleep disorders, fatigue, depression, anxiety, hallucinations, attention, sialorrhea, 
dysphagia, constipation, sexual dysfunction, pain, appetite, sweating) are allowed during 
the study except those for cognition or that have pharmacokinetic or pharmacodynamics 
interactions with levodopa as listed in Table 2.  Medications have to be taken on a regular 
basis and will not be allowed if they are taken on an as needed basis with the exception of 
medication to treat pain post PEG-J procedure.  All medications for the treatment of 
non-motor symptoms must be stable for at least 30 days between V1 and V2 and through 
the Randomization assessments (NMSS and PDSS-2) at the Randomization visit (V3).  
These medications must then also remain stable for the duration of the study.  However, if 
absolutely necessary for a significant medical need related to patient safety, the 
Investigator can make modifications to these medications or add additional medications 
after discussion with the medical monitor.  This will be considered a protocol deviation 
but the subject will not be discontinued from the study.  Caffeine is allowed during the 
screening period and the duration of the study, but the same pattern of consumption 
should be maintained to avoid potential confounds of caffeine.
Required Concomitant Medication, Antibiotics
The use of prophylactic antibiotics is required prior to PEG-J procedure.  At minimum, a 
single dose of a 1st or 3rd generation cephalosporin (or an antibiotic with similar coverage) 
must be administered approximately 30 minutes prior to the PEG-J procedure.


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Prohibited Medications (OMT and LCIG Groups)
The following medications (not comprehensive) are prohibited during the study.


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Table 2.
Prohibited Medications and Treatments
Antipsychotics
Both typical and atypical antipsychotics 
(except quetiapine and clozapine), 
including but not limited to:
Aripiprazole
Fluphenazine
Haloperidol
Perphenazine
Pimozide
Thiothixene
Trifluoperazine
Loxapine
Molindone
Chlorpromazine
Mesoridazine
Thioridazine
Olanzapine
Risperidone
Ziprasidone
Depot neuroleptics
Antiparkinsonian
Apomorphine (PRN injection or continuous 
infusion)
Levodopa-carbidopa-entacapone (LCIG 
group only)
Antihypertensives
Centrally acting (including but not limited 
to reserpine, α-methyldopa, clonidine)
Cinnarizine
Flunarizine
Procedures
Neurosurgical procedure for the treatment 
of Parkinson's disease
Benzodiazepines
Long acting benzodiazepines
Psychostimulants or Sympathomimetics
Psychostimulants (amphetamine, dextroamphetamine, 
methylphenidate, pemoline, etc.)
Weight loss agents (phentermine, sibutramine)
Anticonvulsants
Barbiturates (such as phenobarbital, primidone)
Hydantoins (phenytoin, fosphenytoin)
Succinimides (ethosuximide)
Others (felbamate, lamotrigine, tiagabine,
topiramate, carbamazepine and valproic acid)
Cognition:
Any medication for the treatment of cognition (including 
but not limited to cholinesterase inhibitors or memantine)
Other
Metoclopramide
Oral corticosteroids
Catechol-structured drugs (such as adrenaline, dopamine, 
dobutamine, and isoprenaline)
Rifampicin
Bupropion
Nefazodone
Isoniazide
Tricyclics
MAO-A inhibitors (such as, isocarboxazid, phenelzine, 
tranylcypromine) or nonselective MAO inhibitors
Prochlorperazine
Promethazine
Tetrabenazine
Lithium
As needed use of medications to treat Sleep Disorders 
(not a comprehensive list): 
Short-acting benzodiazepines
Sedating Anti-histamines (also prohibited for PRN use for 
allergic reaction)
Anti-depressants


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5.2.3.3
Rescue Therapy (LCIG Group Only)
After NJ and/or PEG-J placement, subjects randomized to LCIG should fill a prescription 
provided by the Investigator for oral LC-IR tablets in case oral rescue therapy is needed.  
Once LCIG treatment has been initiated, the prescribed oral LC-IR rescue tablets should 
only be used during scheduled LCIG use (16-hour infusion) in case of serious medical 
needs such as the rapid deterioration of motor symptoms that does not respond to an extra 
dose of LCIG.  The subject should be instructed to record all oral levodopa tablets on the 
Subject Dosing Diary on the assigned days.
5.2.3.4
Post Infusion Night Time Therapy (LCIG Group Only)
Those subjects randomized to the LCIG group will be permitted to self-administer their 
typical night-time regimen of oral LC-IR or levodopa-carbidopa continuous-release 
(LC-CR) following the daily discontinuation of the 16-hour infusion, only if they were 
taking this during the 30 day stable medication period during screening and the dose must 
remain unchanged.  (The Investigator will provide a prescription for the doses of oral 
LC-IR or LC-CR that the subject takes on a regular nightly basis.)  After the nightly 
discontinuation of LCIG drug administration, levodopa-DDI tablets may be taken up to 
two hours (for oral LC-IR) or 4 hours (for oral LC-CR) prior to the administration of the 
next morning dose of LCIG and should not be counted as rescue.  The subject should 
record all oral levodopa-carbidopa tablets on the Subject Dosing Diary on the assigned 
days.
Those subjects randomized to the OMT group will remain on their normal, stable 
nighttime regimen if applicable.
5.2.3.5
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Woman of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.


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●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
Male subjects who are sexually active with a WOCBP, even if the male subject has 
undergone a successful vasectomy, must agree from Study Day 1 through at least 4 weeks 
after the last dose of study drug to use condoms and his female partner(s) must use at least 
one of the contraceptive measures (as defined in the protocol for female study subjects of 
childbearing potential).
Male subject agrees not to donate sperm from Study Day 1 through at least 4 weeks after 
the last dose of study drug.


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5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
After a subject has signed the Informed Consent, the study activities described in Table 3
will be completed.  Subject visit days should ideally match the target clinic visit days.  
Every attempt should be made to bring the subject back on the target visit day.  A ± 3 day 
visit window will be allowed as necessary beginning with the Week 2 visit and a ± 7 day 
visit window will be allowed as necessary beginning with the Week 6 visit.  All attempts 
should be made to return the subject to the planned visit schedule (e.g., if the subject is 
two days late for a Study Visit, the scheduling of the next visit date should be based on 
the original planned visit date).  All scheduled visits are calculated based on Study Day 1 
(NJ and/ or PEG-J Placement Day for subjects randomized to LCIG and day after 
randomization for subjects randomized to OMT).


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Table 3.
Study Activities
OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Visit Number for OMT/LCIG
V1
V2c
(Optional)
V3
V4d
V5
V6
V7
V8
V9
Every 6 
and 
12 Weeks
Informed Consente
X
Medical/Neurological/PD Historyf
X
Concomitant Medication (including anti-
PD and NMS medications)
X
X
X
X
X
X
X
X
X
X
Anti-PD Medication History
X
NMS Medication Historyg
X
MMSE (Mini-Mental State Examination)
X
Sleep Attacks Questionnaire
X
X
X
X
X
X
X
X
Physical Examinationh
X
X
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
X
Dermatological Examh
X
X
GI Examh
X
NJ or PEG-J decision 
X
Nasojejunal Tube Placement/Titrationi
(Optional)
X
PEG-J Placement Procedurej
X


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Table 3.
Study Activities (Continued)
OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Radiological Check of Tube Placementj
X
PEG-J Site (Stoma) Check
Xk
X
X
X
X
X
X
Vital Signsl/Weight
X
X
X
X
X
X
X
X
X
X
Heightm
X
ECG
X
X
X
Clinical Labsn (+ urinalysis)n
X
X
Xn
X
X
Urine Drug/Alcohol Screen
X
Special Laboratory Testso
X
X
X
X
X
Pregnancy Testp
X
X
X
X
X
MIDI (Minnesota Impulsive Disorders 
Interview)
X
X
X
X
X
X
X
X
X
C-SSRSq
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Product Complaints
X
X
X
X
X
X
X
X
NMSS (Non-Motor Symptom Scale)
X
X
X
X
PDSS-2 (Modified Parkinson's Disease 
Sleep Scale)
X
X
X
X
UPDRS Parts I – Vr
X
X
X
X
X


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Table 3.
Study Activities (Continued)
OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
CGI-C (Clinical Global Impression  of 
Change)
X
PGIC
X
PDQ-8 (Parkinson's Disease 
Questionnaire-8)
X
X
X
X
MoCA (Montreal Cognitive Assessment)
X
X
X
X
PAS (Parkinson Anxiety Scale)
X
X
X
X
GDS-15 (Geriatric Depression Scale)
X
X
X
X
King's PD Pain Scale
X
X
X
X
Dose Titration Diarys
X
Subject Dosing/Diary Completion
X
X
X
X
X
LCIG System and Pump Training 
(Subject and Caregiver)
X
X
OMT and LCIG Administration
X
X
X
X
X
X
LCIG Titration
X
X
X
X
X
X
X
X
Study Drug Prescription Record (LCIG 
group only)
X
X
X
X
X
X
X
Removal of PEG-J
Xt
LCIG Cassettes Dispensed and/or 
Returned
X
X
X
X
X
X
X
Xu
X


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Table 3.
Study Activities (Continued)
V = Visit; D = Day; FU = Follow-Up; Wk = Week
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG.  
b.
Applicable only to LCIG subjects who complete LCIG study treatment and will transition to commercial LCIG.  Subjects will return every 6 weeks to return used LCIG 
cassettes and be dispensed cassettes.  Safety assessments will be completed every 12 weeks until subjects' transition to commercial LCIG.
c.
Visit 2 is optional and is based on the Investigator's discretion of individual subject need during stabilization of anti-PD medications and medications to treat NMS.
d.
Visit 4 for LCIG Treatment (LCIGT) group only.
e.
Study-related assessments, procedures or activities may not occur prior to subject completing signed informed consent process.  
f.
Update Medical/Neurological/PD History with any findings from Labs, Dermatologists, etc.
g.
NMS Medication History is to be collected at V1.  These include but are not limited to medications used for the treatment of the 9 NMS domains of experience of 
cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, GI tract, urinary, sexual function, and miscellaneous (pain, 
taste/smell, weight change, excessive sweating) should be collected.
h.
At Screening Visit 1 and 2 and Randomization Visit 3 a full physical examination will be performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.  On or prior to Visit 2, the Investigator and GI/surgeon or interventional radiologist, or their designated qualified personnel will thoroughly evaluate the subject's risk of 
undergoing PEG-J procedure.  The dermatological exam will be performed prior to Visit 2.  If a suspicious lesion is present, a biopsy should be obtained for proper diagnosis 
and confirmation that lesion does not meet exclusion criteria.
i.
For subjects randomized to LCIG, a temporary NJ tube may be used to optimize the dose of LCIG before treatment with a PEG-J is started. The NJ test phase should not last 
longer than 7 days.  Following the NJ test phase, a PEG-J will be performed by a gastroenterologist proceduralist or surgeon.  Total time to titration via NJ and PEG-J should 
not exceed 14 days.  Alternatively, subjects may proceed directly to placement of PEG-J if deemed appropriate by investigator.  The number of days to titrate will vary for 
each subject.
j.
LCIG group only.  Radiological check of NJ and PEG-J to determine correct location should occur prior to LCIG infusion initiation and prior to restart of LCIG post PEG-J 
placement.  Placement can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
k.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG.
l.
On the day of the first LCIG infusion, orthostatic vital signs should be obtained at 0, 1, 2 and 3 hours post initial LCIG start.  An attempt should be made to obtain all other 
vital signs at a consistent time of day.  Vital signs should be repeated when PEG-J inserted.
m.
Height will be measured at Visit 1 only.


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Table 3.
Study Activities (Continued)
n.
PT/PTT will be performed at Screening Visits 1 and 3. In the event the PT/PTT result at V3 is abnormal the subject should not proceed with the NJ and/or PEG-J placement 
and should contact the medical monitor.
o.
Special labs to detect vitamin deficiencies, listed in Table 4, will be performed at the times indicated in Table 3.  If at any time during the study a subject displays symptoms 
of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is appropriate for further evaluation of polyneuropathy 
symptoms.  Thyroid function tests will be done at Screening Visit 1 only.
p.
Pregnancy Testing WOCBP must have a negative serum pregnancy test result at Screening, and a negative urine pregnancy test at Study Day 1.  Monthly pregnancy testing 
should be performed during treatment, including at the last dose and until 5 × the half-life of the AbbVie product.
q.
The "Baseline/Screening" C-SSRS will be the first assessment scale administered to the subject.  At each subsequent visit, the "Since Last Visit" C-SSRS scale should be 
administered.
r.
At V1, the UPDRS Part III is conducted in the on/off state, all other times in the on state.  During Visit 1 the UPDRS Part III will be done during practically defined "Off" 
time and best "On" time.  The practically defined "Off" time UPDRS will be done in the morning prior to the subject taking their first daily dose of anti-PD medication.  At a 
minimum a subject should be 8 hours without anti-PD medication before the UPDRS is completed.  The best "On" time rating should be done approximately 1 to 2 hours post 
any morning dose of study drug or PD medications but prior to lunch.  If possible, the UPDRS should be done at the same time of day throughout the trial.  The "Off" time 
UPDRS will only be done during Screening; at all other times a complete UPDRS (Parts I through V) will be done during "On" time.
s.
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a tool to achieve dose optimization.  In the event it is used it should be completed 
hourly until the dose is optimized and then once AM and once PM it will be completed until the subject is discharged.  All adjustments can be recorded on the Dose Titration 
Diary allowing the Investigator to appropriately adjust, if needed, the following day's morning dose, continuous infusion rate and extra dose until the subject is optimized.
t.
PEG-J removal will be complete 1 week before follow up visit.
u.
At Week 27 follow up visit LCIG cassettes return only.
Note:
All applicable clinical, safety, health outcome and cognition assessments will be administered only by individuals qualified by the Sponsor.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 3 are discussed in this section, with the exception 
of the collection of adverse event information and product complaints (Section 6.0).
Due to the length of assessments on Visit 1, assessments may be performed over 2 days.  
Informed Consent
Voluntary written informed consent must be obtained from each subject (and if 
appropriate, their caregiver) prior to performing any study-related procedures.  
Consenting will be performed according to local regulations.
Subject Medical and Neurological History
A complete medical history, including alcohol, drug, tobacco and nicotine-containing 
product use histories will be taken at the time indicated in Table 3.  Additionally, chronic 
disorders (e.g., diabetes and hay fever) that began prior to Screening and are still present 
at Screening should be recorded on the Medical History Form.  The Medical History 
obtained at V1 will serve as the baseline for clinical assessment.  All psychiatric, 
neurological, behavioral and/or cognitive diagnosis should be reported.  Updates should 
be made to the Medical/Neurological/PD History with any findings from Labs, 
Dermatologists, etc.
Subject Parkinson's Disease and NMS Treatment History
In order to qualify for enrollment in the study, the subject should provide the Investigator 
with a comprehensive history of their past anti-PD and NMS drug treatments.  This 
should be done according to the patient and/or caregiver recollection as well as available 
history in a subject's chart.  
NMS Medication History is to be collected at V1.  These include but are not limited to 
medications used for the treatment of the 9 NMS domains of:  experience of 
cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, 


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attention/memory, GI tract, urinary, sexual function, and miscellaneous (pain, taste/smell, 
weight change excessive sweating). 
A careful review of the subject's PD history, previous and current PD treatments should
be performed by the Investigator (e.g., dosages, frequency of administration, duration of 
treatment, assessment and evaluation of the subject's response to those previous PD 
treatments) to determine if the subject is eligible for study participation.  
Mini-Mental State Examination (MMSE)
The MMSE44 is a brief, 30-point questionnaire, administered by a trained rater, which 
provides a quantitative measure of cognitive mental status in adults and is widely used to 
screen for cognitive impairment and to estimate the severity of cognitive impairment at a 
given point in time, to follow the course of cognitive changes in a patient over time, and 
to document response to treatment.  In this study, MMSE will be used to screen for 
cognitive impairment.  The subject must have a score ≥ 24 at Screening Visit 1 to be 
eligible for study participation.  Lower scores indicate greater impairment.  The MMSE 
will be administered at Visit 1 as indicated in Table 3.
Sleep Attack Assessment
To prospectively monitor for possible development of sleep attacks, the subject will be 
evaluated for sleep attacks at the times indicated in Table 3.  The subject will be asked the 
following Sleep Attack Assessment questions:
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 at rest, without any previous 
warning of sleepiness (e.g., feeling tired)?
●
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?
During the Screening Period, subjects should be asked to answer these questions based on 
their experiences during the three months prior to Screening Visit 1.  During the 
Screening Period, if the subject is currently or has been recently experiencing sleep 
attacks, they will be excluded from participation in the study and referred for appropriate 
follow-up care if the Investigator feels these are clinically significant.  The assessment of 
Sleep Attacks completed at the Screening Visit 1 will serve as baseline for clinical 
assessment.
Physical Examination
At Screening V1, V2 and Randomization V3 a full physical examination will be 
performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.
Neurological Examination
A Neurological Examination focusing on symptoms and signs of polyneuropathy (light 
touch and pinprick sensation, vibratory sensation), deep tendon reflexes, and strength 
assessments will be performed at the times indicated in Table 3.  The Neurological 
Examination should be bilateral and be done during the subject's "On" time.
Any abnormalities or symptoms identified at Visits 1, 2 and 3 will not be recorded as 
adverse events but will be recorded in Medical History eCRF.  Any new abnormalities or 
symptoms or symptoms that change in severity or frequency following randomization for 
the OMT group and the first dose of IP for the LCIG group will be recorded as adverse 
events.
The Neurological Examination will assess:


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●
Cranial nerves – assessment of cranial nerves II – XII
●
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
The Neurological Examination performed at Visit 1, will serve as baseline for clinical 
assessment.
Dermatological Assessment
A comprehensive assessment by an experienced dermatologist for the presence of any 
suspicious skin lesions and subsequent evaluation for melanoma will be performed prior 
to V2 and at Week 26/Premature Discontinuation.  If a suspicious lesion is present, a 
biopsy should be obtained for proper diagnosis and confirmation that lesion does not meet 
exclusion criteria.
Positive screens will be exclusionary.
GI Examination
On or prior to V2, the Investigator and GI/surgeon will thoroughly evaluate the subject's 
risk of undergoing PEG-J procedure.
NJ and/or PEG-J Placement (LCIG Group Only)
For subjects randomized to LCIG, a temporary NJ tube may be used to optimize the dose 
of LCIG before treatment with a PEG-J is started.  The NJ test phase should not last 
longer than 7 days.  Following the NJ test phase, a PEG-J will be performed by a 
gastroenterologist proceduralist, or surgeon.  Total time to titration via NJ and PEG-J 
should not exceed 14 days.  Alternatively, subjects may proceed directly to placement of 


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PEG-J if deemed appropriate by investigator.  Total time to titration via the NJ and PEG-J 
should not exceed 14 days.  The number of days to titrate will vary for each subject.
Radiological Check of Tube Placement (LCIG Group Only)
Radiological check of NJ and PEG-J to determine correct location should occur prior to 
LCIG infusion initiation and prior to restart of LCIG post PEG-J placement.  It can also 
be done at any time during treatment if indicated for worsening of Parkinsonian 
symptoms or non-responsiveness to extra doses. 
PEG-Site (Stoma) Check (LCIG Group Only)
Following the PEG-J placement, site personnel will review proper after-care instructions 
and checking of the stoma instructions with the subject and/or care-partner as provided in 
the patient care materials/booklets.
After the initial PEG-J procedure, the PEG-J and stoma must be inspected by a 
gastroenterologist proceduralist/surgeon/qualified radiologist (preferably the physician 
who placed the PEG-J), or their designated qualified personnel 2 – 7 days post PEG-J 
procedure. 
Vital Signs/Weight
Body temperature, orthostatic vital signs and weight will be performed at the times 
indicated in Table 3.  All systolic and diastolic blood pressure and pulse rate 
measurements are to be measured orthostatically.  Orthostatic systolic and diastolic blood 
pressure and pulse rate are to be measured while the subject is supine (after 3 to 
5 minutes) and standing (after 2 minutes).  Study staff should make efforts to measure 
with the same arm and method including recording of arm and method in the subject's 
source documentation.
On the day of the first LCIG infusion, orthostatic vital signs should be obtained at 0, 1, 2 
and 3 hours post initial LCIG start.  An attempt should be made to obtain all other vital 
signs at a consistent time of day.  Vital signs should be repeated when PEG-J inserted.


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Vital signs will include body weight will be measured at the times indicated in Table 3.  
The subject will wear lightweight clothing and no shoes during weighing.
Height
Height will be measured only at V1; the subject will not wear shoes.
12-Lead Electrocardiogram (ECG)
A single 12-lead resting ECG will be obtained at study visits indicated in Table 3.  An 
attempt should be made to obtain all other ECGs at a consistent time of day.
ECGs will be recorded after the subject has been supine for at least 5 minutes.  The 
subject should be instructed to remain completely stationary during the recording, without 
talking, laughing, deep breathing or swallowing during the time of recording (10 seconds).
ECG Data Review 
Site personnel will transmit ECG data to an ECG central laboratory for central processing 
and reading by a qualified cardiologist (central reader) who will independently review 
each ECG.  The central reader will evaluate a single ECG lead (Lead II, with V5 or V2 [in 
that order] evaluated if Lead II cannot be evaluated).  Heart rate, RR interval, PR interval, 
QRS duration and QT interval will be measured for each ECG with 3 to 5 beats.  QT 
interval corrected for heart rate (QTc) will be determined using Fridericia's correction 
method (QTcF).
The central reader will also provide the interpretation of the ECG (i.e., "Normal" or 
"Abnormal").  The central ECG laboratory will send the ECG report to the site within 
3 business days.  The Investigator (or physician designee) will review the central reader's
report/assessment and document his/her review by signing and dating the central ECG 
laboratory report.  Only the central ECG laboratory's data will be collected into the 
database.  The Investigator should review and reconcile if necessary his/her interpretation 
of the ECG (normal/abnormal) with the central ECG laboratory in case of relevant 
divergent assessments and reconcile as he/she determines is appropriate.


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The original ECG tracing and the central reader's interpretation, each with the 
Investigator's signature and date, will be retained in the subject's records at the study site 
as source documents.
Clinical Laboratory Tests
A certified laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All clinical laboratory samples will be collected as indicated in Table 3
(see Table 4 for list of laboratory evaluations).  The laboratory test results obtained at 
Visit 1 will serve as baseline for clinical assessment.  All clinical laboratory samples 
should be collected after the completion of all other assessments.  The Investigator must 
review the laboratory assessments (initialed and dated) after the receipt of results.
All laboratory abnormalities that occur during the study must be evaluated by the 
investigator to determine if they indicate a new disease process, an exacerbation or 
worsening of an existing condition, or require further action to be taken and therefore may 
need to be reported as adverse events.  Accordingly, for any values outside of the 
reference range, the Investigator will indicate on the report if the result is Clinically 
Significant (CS) or Not Clinically Significant (NCS).  If a laboratory abnormality meets 
criteria for a Potentially Clinically Significant (PCS) laboratory value, as defined in 
Appendix D, the investigator must either report an associated adverse event or document 
in source the reason(s) the finding was not considered an adverse event.
The PT/PTT will be performed at Screening Visits 1 and 3. In the event the PT/PTT 
result at V3 is abnormal the subject should not proceed with the NJ and/or PEG-J 
placement and should contact the medical monitor.
Any laboratory value that remains abnormal at Premature Discontinuation/End of Study 
and was judged to be clinically significant will be followed according to accepted medical 
standards until resolution of the abnormality.


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Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
Platelet count (estimate not
acceptable)
White Blood Cell (WBC) count
Mean corpuscular volume 
(MCV)
Mean corpuscular hemoglobin 
(MCHC)
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
PT/INR (Prothrombine 
Time/International 
Normalized Ratio)a
PTT (Partial Thromboplastin 
Time)a
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (ALT)
Serum glutamic-oxaloacetic
transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Albumin
Chloride
Creatine kinase
Gamma-glutamyl transpeptidase 
(GGT)
Bicarbonate
Lactate dehydrogenase LDH
Pregnancy testb
Beta human chorionic 
gonadotropin (hCG)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic Examination
Urine pregnancy Testc
Drug/Alcohol screening:d
Ethanol
U-etylglucuronide 
(U-Etg)
U-etylsulphate (U-Ets)
Cannabinoids
Barbiturates
Benzodiazepines
Opiates
Methadone
Cocaine
Amphetamines
Special Testsd
Thyroid Function 
Testse
Vitamin B12
f
Vitamin B6
f
Folic Acid
Methylmalonic Acid 
(MMA)f
Homocysteinef
a.
Visits 1 and 3.  In the event the PT/PTT result at V3 is abnormal the subject should not proceed with the NJ and/or 
PEG-J placement and should contact the medical monitor.
b.
For all females of childbearing potential; a serum pregnancy test will be performed at Visit 1 and Premature 
Discontinuation/End of Study.  Additional testing may be required per local regulations.  A negative serum 
pregnancy result is required before oral study drug is dispensed.
c.
For all females of childbearing potential; a negative urine pregnancy test result is required prior to the PEG-J 
placement procedure and any radiological procedures.
d.
Only performed at Visit 1.  Positive Alcohol test is not exclusionary criteria.
e.
Includes TSH and free T4 (Visit 1 only).


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Table 4.
Clinical Laboratory Tests (Continued)
f.
Special labs to detect vitamin deficiencies, including:  Vitamin B12, Vitamin B6, folic acid, MMA, and 
homocysteine levels will be performed at the times indicated in Table 3.  Abnormal Vitamin B12 of questionable 
clinical significance (indeterminate or low normal results at screening) require MMA and homocysteine laboratory 
assessments be reviewed for determination of B12 deficiency prior to entry into the study.  If at any time during the 
study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other 
assessment that the Investigator feels is appropriate for further evaluation of polyneuropathy symptoms.
Urine Screens for Drugs of Abuse and Alcohol
A urine screen for drugs of abuse and medical marijuana and alcohol will be performed at 
V1 (Table 4).
The panel for drugs to be tested will minimally include the tests listed Table 4.  The urine 
drug screen analysis at Visit 1 will be performed by the certified central laboratory chosen 
for the study, and will be used for screening purposes.
The alcohol lab values will be recorded, as required by VHP and will be use as 
quantitative value for assessment of risk factors (e.g., polyneuropathy, etc.).
Special Laboratory Tests
Special labs to detect vitamin deficiencies, including:  Vitamin B12, Vitamin B6, folic acid, 
MMA, and homocysteine levels will be performed at the times indicated in Table 3.  
Abnormal Vitamin B12 of questionable clinical significance (indeterminate or low normal 
results at screening) require MMA and homocysteine laboratory assessments be reviewed 
for determination of B12 deficiency prior to entry into the study.  Only labs at Visit 1 are 
exclusionary.  If at any time during the study a subject displays symptoms of 
polyneuropathy, the Investigator must perform this lab panel and any other assessment 
that the Investigator feels is appropriate for further evaluation of polyneuropathy 
symptoms.  Thyroid function tests will be done at Visit 1 only.
Pregnancy Testing
●
WOCBP must have a negative serum/urine pregnancy test result at Screening, 
and a negative serum/urine pregnancy test at Study Day 1.  Monthly pregnancy 


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testing should be performed during treatment, including at the last dose and 
until 5 × the half-life of the AbbVie product.
●
Subjects with borderline pregnancy tests at Screening must have a serum 
pregnancy test ≥ 3 days later to document continued lack of a positive result.
●
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy 
testing at any time.
Montreal Cognitive Assessment (MoCA)
The MoCA has been widely utilized in clinical settings to study cognition in PD.  It was 
originally developed as a screening tool to assess mild cognitive impairment in the general 
population.  The MoCA will be administered to assess for cognitive impairment and will 
be administered at Visits 3, 6, 7 and 8.  The scale assesses seven cognitive domains, 
including visuospatial/executive, naming, memory/delayed recall, attention, language, 
abstraction and orientation.  The maximum total score that can be obtained is 30 and a cut 
off score of 25/26 on MoCA has demonstrated a diagnostic sensitivity of 90% for 
individuals diagnosed with mild cognitive impairment.  Additionally the movement 
disorder society has recommended the use of this scale due to its acceptable clinimetric 
properties45 and diagnostic utility.
Minnesota Impulsive Disorders Interview (MIDI)
To monitor for development of intense impulsive behavior, the Minnesota Impulsive 
Disorders Interview (MIDI)46 will be administered at the times indicated in Table 3 or 
whenever relevant symptoms emerge.  The entire interview is to be completed at V1.  If 
the subject's impulsivity during the Screening Period is judged to be clinically significant 
in the judgment of the Investigator, they will be excluded from participation in the study 
and referred for appropriate follow-up care.  Any subject noted to have intense impulsive 
behavior during the study as assessed by the MIDI, or via clinical interview, will be 
evaluated immediately by the Investigator.  The study designated physician should also be 
notified.  The MIDI will be administered as indicated in Table 3.


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Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS)47 is a systematically administered 
instrument 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.
Any subject noted to have suicidal ideation with plan within the last year, either via 
answering "yes" to question 4 and/or question 5 to the suicidal ideation portion of the 
C-SSRS, or via clinical interview, will be evaluated immediately by the Investigator.  The 
study designated physician will also be notified.  In addition, if the subject expresses 
suicidal ideation at any time during the study, the Investigator should be immediately 
notified as well as the study designated physician. 
Under no circumstances should a subject who has positively endorsed or expressed 
suicidal ideation 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 visit, the "Since Last Visit" C-SSRS scale should be 
administered.
The C-SSRS will be administered at the times outlined in Table 3.
Non-Motor Symptom Scale (NMSS)
Non-motor symptoms associated with Parkinson's disease can result in substantial patient 
burden.  The NMSS is a comprehensive validated tool measuring a broad range of 
non-motor symptoms in PD patients.  The scale is aimed to be practical and quantitative, 
encompassing the whole range of non-motor symptoms experienced by people with PD.  
The NMSS measures the frequency and severity of these symptoms and is comprised of 
30 questions that cover 9 domains of patient symptom experience (cardiovascular/falls, 


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sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, GI 
tract, urinary, sexual function, and miscellaneous [pain, taste/smell, weight change, 
excessive sweating]).48,49  The NMSS measures the burden of non-motor symptoms by 
weighting each symptom by its frequency and severity; thereby, providing a quantitative 
measure that captures infrequent but severe symptoms (e.g., hallucinations) and less 
serious but frequent symptoms (e.g., fatigue, constipation) and provides the overall global 
burden for patients.  Scores are calculated for each domain as well as a total score.  
Severity and frequency are rated using a 4-point scale ranging from 0 (none) to 3 (severe; 
major source of distress or disturbance to subject) for severity and from 1 (rarely) to 
4 (very frequent [daily or all the time]) for frequency.  The total NMSS score ranges from 
0 to 360.  A negative change from Baseline to end of Maintenance indicates an 
improvement in NMSS.  It is required that only trained and certified health professionals 
will administer the scale.  For this study the NMSS will be performed by an approved, 
trained, blinded, central rater, who should be a specialist on movement disorders with 
previous experience using the NMSS scale in advanced PD patients.  To be qualified by 
the Sponsor and the rater vendor, all raters must have participated in the Rater Training 
and have a current valid Rater Certificate.  The qualified rater will complete the NMSS at 
the times indicated in Table 3.
PDSS-2
Although a number of scales exist in evaluating sleep disturbances, only 3 are endorsed 
and recommended by the Movement Disorders Society.50  One such scale specific for 
Parkinson's disease is the Parkinson's Disease Sleep Scale (PDSS), which has been 
modified to the PDSS-2.  The purpose of the PDSS-2 scale is to characterize the various 
aspects of nocturnal sleep problems in PD patients.  The PDSS-2 instrument has been 
shown to be reliable, valid, precise, and a potentially treatment responsive tool for 
measuring nocturnal disabilities and sleep disorders in PD.51  PDSS-2 consists of 
15 questions evaluating motor and NMS at night and upon wakening, as well as disturbed 
sleep grouped into 3 domains:  motor symptoms at night (5 items), PD symptoms at night 
(5 items), and disturbed sleep (5 items).  Specifically, questions assess overall sleep 


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quality, insomnia, sleep fragmentation, RLS and PLMS, RBD, hallucinations, nocturia, 
nocturnal immobility, pain and cramps, morning akinesia, cramps and tremor, and sleep 
apnea.  The PDSS-2 was developed from the PDSS based upon the need for a 
treatment-measuring tool containing PD-specific sleep disorders.  The instrument was 
extended to address specific sleep disturbances such as RLS, akinesia, pain, and sleep 
apnea.  Daytime sleepiness was removed from the PDSS-2, as it is a more complex PD 
symptom.  To increase ease of use, the visual analogue scale of the PDSS was 
transformed into a frequency measure in the PDSS-2.  The frequency is assessed for the 
15 sleep problems based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very 
often]).  Scores are calculated for each domain as well as a total score.  The recall period 
is for the past week.  For this study the PDSS-2 will be performed by an approved, 
trained, blinded central rater, who should be specialist on movement disorders with 
previous experience using the NMSS scale in advanced PD patients.  To be qualified by 
the Sponsor and the rater vendor, all raters must have participated in the Rater Training 
and have a current valid Rater Certificate.  The qualified rater will complete the PDSS-2 
at the times indicated in Table 3.
The PDSS-2 will be completed at the times indicated in Table 3. 
Unified Parkinson's Disease Rating Scale (UPDRS)
The Unified Parkinson's Disease Rating Scale (UPDRS)52 is an Investigator-used rating 
tool to follow the longitudinal course of Parkinson's disease.  Every effort should be made 
by the Investigative sites to ensure that each subject is rated by the same rater throughout 
the subject's participation in the study.  The UPDRS assessment will be performed by an 
approved, trained rater.  To be qualified by the Sponsor and the rater vendor, 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


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●
Part III – Motor Examination
●
Part IV – Complications of Therapy (including dyskinesias)
●
Part V – Modified Hoehn and Yahr Staging
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 of the UPDRS will be totaled to 
evaluate dyskinesias.
During Visit 1 the UPDRS Part III will be done during practically defined "Off" time and 
best "On" time.  The practically defined "Off" time UPDRS will be done in the morning 
prior to the subject taking their first daily dose of anti-PD medication.  The best "On" time 
rating should be done approximately 1 to 2 hours post any morning dose of study drug or 
PD medications but prior to lunch.  If possible, the UPDRS should be done at the same 
time of day throughout the trial.  The "Off" time UPDRS will only be done during 
Screening; at all other times a complete UPDRS (Parts 1 through 5) will be done during 
"On" time.
The UPDRS will be obtained at the times indicated in Table 3.
Health Outcome Measurements
Clinical Global Impression of Change (CGI-C)
The CGI-C is a clinician's rating scale for assessing Global Improvement or Change.  The 
CGI-C rates improvement by 7 categories:  very much improved, much improved, 
minimally improved, no change, minimally worse, much worse, very much worse.  
Proportion of responders who had at least "minimally improved" in CGI-C ratings will be 
assessed.
A qualified rater will administer the CGI-C to the subject at the times indicated in Table 3.


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Patients' Global Impression of Change (PGIC)
The PGIC53 is a 7-point response scale.  The subject will be asked by the Investigator or 
qualified designee to rate their change in status using the following 7-point scale:  
1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 
5 = Minimally worse, 6 = Much worse, 7 = Very much worse.
The responses of "Very much improved," "Much improved" and "Minimally improved" 
on the PGIC will be used to define responders.  A qualified rater will administer the PGIC 
to the subject at the times indicated in Table 3.
Parkinson's Disease Questionnaire (PDQ-8)
The PDQ-854 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-8 is a self-administered questionnaire.  Each item is scored on 
the following 5-point scale:  0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 
4 = Always (or cannot do at all, if applicable).
Higher scores are consistently associated with the more severe symptoms of the disease 
such as tremors and stiffness.  The results are presented as eight discrete domain scores 
and as a summary index.  The PDQ-8 domain scores and summary index range from 0 to 
100, where lower scores indicate a better perceived health status.
A qualified rater will administer the PDQ-8 to the subject at the times indicated in 
Table 3.
Parkinson Anxiety Scale (PAS)
The Parkinson Anxiety Scale (PAS) is a new scale developed specifically to measure 
severity in anxiety in Parkinson's disease.  Lack of adequate validation data in the existing 
anxiety scales led to the development of the PAS.  The PAS is a brief scale designed to 
measure anxiety in PD, rated by patients or clinicians.  It contains three dimensions: 
persistent anxiety, episodic anxiety, and avoidance behavior.  It is an easy and brief to 


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administer, and has better clinimetric properties than existing anxiety rating scales.55  
Additionally a recent study has found that the PAS modified dimensions A and B provide 
valid and reliable measures of anxiety in PD that are comparable across raters.56  A 
qualified rater will administer the PAS to the subject at Visits 3, 6, 7 and 8.
Geriatric Depression Scale (GDS-15)
The Geriatric Depression Scale (GDS) is a short, self-report reliable and valid screening 
instrument for depression in the elderly.  The response items are in a "Yes/No" format.  
The GDS was originally developed as a 30-item instrument but it was time-consuming 
and difficult for some patients to complete hence a 15-item version of the GDS was 
developed.  The shortened form consists of 15 items chosen from the Geriatric Depression 
Scale-Long Form (GDS-L).  These 15 items were chosen because of their high correlation 
with depressive symptoms in previous validation studies.57  The GDS-15 has adequate 
discriminant validity for the diagnosis of major and minor depressive disorder.58  Of the 
15 items, 10 indicate the presence of depression when answered positively while the other 
5 are indicative of depression when answered negatively.  The GDS items focus on the 
psychological aspects of depression, thus avoiding symptom overlap with other disorders 
or aging in general.  The GDS-15 can be completed in approximately 5 to 7 minutes, 
making it ideal for patients who are easily fatigued or are limited in their ability to 
concentrate for longer periods of time.  A qualified rater will administer the GDS-15 to 
the subject to assess depression at Visits 3, 6, 7 and 8.
King's PD Pain Scale
The King's PD Pain Scale is an easy to administer novel clinical PD specific pain scale 
developed with a focus on sub classification of nociceptive and neuropathic pain.  It was 
specifically developed to assess pain among Parkinson's disease patients since no 
validated PD specific scales existed to characterize the various types of pain in PD.  The 
scale consists of seven domains of pain including musculoskeletal, chronic, fluctuation 
related, nocturnal, oro-facial, local limb pain/edema/swelling and radicular pain.  The 
scale measures the frequency and severity of these symptoms.  The clinimetric properties 


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of this instrument have been recently evaluated.59  A qualified rater will administer the 
King's PD Pain Scale to the subject to assess for PD specific pain at Visits 3, 6, 7 and 8.59
Titration Visits (LCIG Group Only)
Dose Titration Diary and LCIG Prescription Record (LCIG Group Only)
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a 
tool to achieve dose optimization.  In the event it is used it should be completed hourly 
until the dose is optimized and then once AM and once PM it will be completed until the 
subject is discharged.  All adjustments can be recorded on the Dose Titration Diary 
allowing the Investigator to appropriately adjust, if needed, the following day's morning
dose, continuous infusion rate and extra dose until the subject is optimized.
The subject's pump settings for the first infusion of LCIG, the pump settings at the 
conclusion of each calendar day are to be recorded on the appropriate eCRF.
Following the initial titration period, the site should record the subject's pump settings 
(morning dose in mL, continuous infusion rate in mL/hr, and lock level) at the conclusion 
of each clinic visit on the study drug prescription record.
Subject Dosing Diary (LCIG and OMT Groups)
The subject dosing diary should be completed during the 72-hour period (3 days) prior to 
each clinic visit, as indicated in Table 3.  Subjects should be reminded with a phone call 
prior to each visit to complete the Subject Dosing Diaries and to reinforce the importance 
of Subject Dosing Diary completion.
Subjects in the LCIG group will record the date and actual clock time of the LCIG pump 
start and pump stop as well as LCIG extra doses in the diary.  In addition, the subject will 
be instructed to record all oral levodopa-carbidopa taken on the Subject Dosing Diary 
days.


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Subjects in the OMT group will record all anti-parkinsonian medications taken on the 
Subject Dosing Diary days in the diary.
5.3.1.2
Rater Requirements
All applicable clinical, safety, health outcome and cognition assessments will be 
administered only by individuals qualified by the Sponsor.  Every effort must be made by 
the Investigative sites to ensure that each subject is rated by the same rater throughout the 
subject's participation in the study.
Prior to administration of respective scale(s), designated raters will be trained on and 
certified (if appropriate) in the use of all the scales used in this study.  The objective of 
this certification/training is to ensure uniformity across sites in the administration and 
scoring of these assessments.
The Sponsor, in conjunction with the approved rater training vendor, if applicable, will 
determine the minimum rater qualifications for each of the rating scales.  All raters must 
meet these qualifications prior to participation in the training process.  The names and 
qualifications of all site personnel to be involved in rating scale administration will be 
submitted for approval upon site selection.  The qualifications of the raters will be verified 
through the training vendor.  Qualified raters will be trained and tested for competency 
and, if they meet established requirements, certified at the Investigator meeting.  
Individual exceptions to these requirements must be approved by the Sponsor via the 
training vendor if applicable.
Only those persons who have been trained as raters for this study may rate the subjects.  
Raters who cannot participate in the initial pre-study training or who become involved in 
the study at a later time will not be permitted to perform study ratings until they have 
satisfactorily completed an individualized training program designed by the rater training 
vendor if applicable, approved by AbbVie, and supervised by the Investigator or his/her 
designee.  Raters may be reassessed periodically throughout the study.


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Specific Rater Training Requirements
The UPDRS will be administered only by individuals qualified by the Sponsor and the 
rater training vendor.  Prior to administration, designated raters (Investigator or an 
experienced and medically qualified study site designee [e.g., NP, PA, DO, MD, or PhD] 
assigned by the Investigator) will 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 the scale.
The Sponsor, in conjunction with the rater training vendor, will determine the minimum 
rater qualifications for the rating scale.  All raters must meet these qualifications prior to 
participation in the training process.  The names and qualifications of all site personnel to 
be involved in the UPDRS, rating scale administration will be submitted for approval 
upon site selection.  The qualifications of the raters will be verified through the rater 
training vendor.  Qualified raters will be trained and tested for competency and, if they 
meet established requirements, will be certified.  Individual exceptions to these 
requirements must be approved by the Sponsor via the rater training vendor.
Only those persons who have been trained and certified as raters for this study may rate 
the subjects.  Raters who cannot participate in the initial pre-study certification/training or 
who become involved in the study at a later time will not be permitted to perform study 
ratings until they have satisfactorily completed an individualized certification/training 
program designed by the rater training vendor, approved by the Sponsor, and supervised 
by the Investigator or his/her designee.  It is the responsibility of the Investigator to ensure 
the raters at his/her site are appropriately trained and certified to administer the selected 
rating scales.  Raters will be reassessed periodically throughout the study.
Blinded Rater Training Requirements
The NMSS and PDSS-2 will be administered by blinded central raters on the respective 
scales at Randomization, V3.  This will serve as the baseline for clinical assessment.  
They will also administer both scales at Weeks 6, 12, and 26.  


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It is required that only trained and certified specialists on movement disorders with 
previous experience using the NMSS scale in advanced PD patients will serve as blinded 
central raters and administer NMSS and PDSS-2.  The blinded raters will not have access 
to the results of other study assessments or medical records for the subject and will not 
participate in the care or management of the subject.  Each rating is based exclusively on 
an interview with the subject (and the subject's caregiver when available).
The blinded central rater will complete the NMSS and PDSS-2 at the times indicated in 
Table 3 with the baseline assessment occurring at Screening Visit 3.
Rater Training Requirements for All Other Secondary Scales
Appropriate study site personnel will be trained on the use of all other secondary scales 
used in this study.  Raters who become involved in the study after the Investigator's 
meeting will not be permitted to perform any study-specified ratings until they have 
satisfactorily completed the appropriate training program as designated by the Sponsor.  It 
is the responsibility of the Investigator to ensure the raters at his/her site are appropriately 
trained to administer all rating scales.
5.3.1.3
Ancillary Support
Sites will be appropriately trained and provided support on the initiation and titration of 
LCIG prior to subject enrollment of the first subject at each site. 
Duodopa Study Specialist (DSS)
The Sponsor may provide ancillary support to the study sites by utilizing a Duodopa 
Study Specialist (DSS) to provide additional training to the Investigator and site 
personnel.  These DSS' training and consultation services will be similar to those provided 
in the previous Phase 3 program.  DSS services and training are methods of support in the 
implementation of the LCIG administration system at clinical sites.


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The functions of the DSS may include:
●
Provide ongoing education and support to the site personnel (Investigator, 
gastroenterologist, study coordinators, research nurses, titration nurses and 
additional staff) throughout the enrollment period, initiation, titration  and rest 
of the clinical trial
●
Facilitate the implementation of the "Train the Trainer Model" by providing 
initial training to site staff.  The Investigator or the appointed delegate may 
provide ongoing training to new staff.
●
Educate the research site staff on medication, cassettes, 
basic/intermediate/advanced pump function, programming, troubleshooting, 
tubing, and stoma care
●
Educate site personnel (e.g., nurses and physicians) in the proper handling, 
"Best Practices" for placement, and management of PEG-J tube
●
Educate site personnel about Product Complaints and Adverse Events
●
Meet local state and hospital/institution rules, laws, and regulations in regards 
to their role and responsibilities
5.3.2
Drug Concentration Measurements
No drug concentration measurements will be completed during the study.
5.3.3
Efficacy Variables
There will be two alternative primary efficacy variables.
●
Change from baseline to Week 26 in NMSS total score
●
Change from baseline to Week 26 in PDSS-2 total score
Secondary endpoints will consist of the following validated scales:
●
UPDRS total score and section scores during "On" time
●
PDQ-8 summary index and domain scores
●
CGI-C


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●
PGIC
●
PAS
●
GDS-15
●
King's PD Pain Scale
5.3.4
Safety Variables
Safety and tolerability over the course of the study will be assessed by the following 
measurements:
●
Adverse event monitoring
●
Neurological exams
●
Clinical laboratory evaluations
●
Electrocardiogram
●
Vital signs and weight
●
C-SSRS
●
MIDI
●
SAQ
5.3.5
Health Outcome Variables
The following measurements (already described in Section 5.3.3) are considered health 
outcomes:
●
PDQ-8
●
CGI-C
●
UPDRS Parts I and II
●
PGIC
●
PAS
●
GDS-15
●
King's PD Pain Scale


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.  Subjects who withdraw from the study will not be 
replaced.
Subjects may develop adverse events or abnormalities in vital signs, ECGs, physical 
examinations, neurological examinations or laboratory determinations during their 
participation in the study.  If these occur, the Investigator may discontinue a subject from 
the study if, in their clinical judgment, continued participation would result in undue risk 
or further worsening of the condition.
The following adverse events require Premature Discontinuation:
●
Subjects who develop a melanoma during the course of the study should be 
discontinued from participation and referred for appropriate follow-up care
●
Subjects who develop impulsive behavior that is clinically significant, in the 
judgment of the Investigator, should be discontinued from participation in the 
study and referred for appropriate follow-up care
●
As indicated by answering yes to question 4 or 5 on the C-SSRS, subjects 
should be discontinued from participation in the study and referred for 
appropriate follow-up care
●
Subjects who become pregnant should be discontinued from participation in 
the study and referred for appropriate follow-up care
In the event that a subject withdraws or is discontinued from the study after they have 
begun the PEG-J placement procedure, the assessments for a Premature Discontinuation 
Visit should be performed as soon as possible after discontinuation from the study.


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If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the Investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
The Study Termination eCRF must be completed for all subjects who have entered the 
study (i.e., have signed the Informed Consent).  Subjects dropping out prior to 
randomization will be considered Screen Failures and the reason for Screen Failure will 
be entered in the eCRF.  In case of Premature Discontinuation of the subject after 
randomization, the primary reason for Premature Discontinuation will be entered in the 
eCRF.
5.4.2
Removal of the PEG-J (LCIG Group Only)
For subjects randomized to LCIG, in case of premature discontinuation of the subject or 
subject not continuing on commercial treatment, after the PEG-J has been placed, the 
PEG-J should be removed via endoscopy.  The PEG-J should not be removed for 10 to 
14 days after placement or until the stoma-tract is formed.  Institutional standards for 
follow-up care after removal of the PEG-J should be followed.  The tube must be removed 
endoscopically by a qualified gastroenterologist proceduralist or surgeon.  Follow-up visit 
with examination should occur 1 week following the PEG-J removal.
5.4.3
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.


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5.5
Treatments
5.5.1
Treatments Administered
Subjects may be randomized to one of two treatment groups, OMT or LCIG.
5.5.1.1
OMT
Those subjects randomized to OMT at the end of V3 will continue on their current 
anti-PD medication regimen for the duration of the study.  The PI will provide the 
prescription for continued OMT.  PIs should make any effort to keep all anti-PD 
medications and medications to treat NMS stable for the duration of the study.  Changes 
to the OMT arm can be made "if medically justified" or if absolutely indicated for safety 
reasons.  The day after V3 will be considered Day 1 of the treatment period for the OMT 
group.  Subjects in the OMT Group will not have a Visit 4, while visits 5 through 8 will
take place at the end of Weeks 2 through 26 respectively.  All data will be recorded on the 
appropriate eCRF and the assessments completed as in Table 3.
5.5.1.2
LCIG
LCIG is supplied as a homogenous suspension of levodopa (20 mg/mL) and carbidopa 
monohydrate (5 mg/mL) in an aqueous intestinal gel (carboxymethyl cellulose).  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 each day.  At night, after disconnecting the pump, the tubing is flushed 
with potable water.
The total daily dose of infusion LCIG will be composed of three components:  (i) the 
morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses.
Subject dosing is determined individually.  The starting total daily dose of LCIG infusion 
after placement of the PEG-J tube will be based solely on the daily dose of the oral 
levodopa component from the tablets of levodopa-immediate (IR) taken immediately prior 
to NJ (or PEG-J) placement during the 16 hour waking day it was anticipated the subject 


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would be on LCIG therapy.  The rate of LCIG infusion is typically within the range of 1 
to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period 
of 16 consecutive hours.  The PEG-J tube should be disconnected from the infusion pump 
before bedtime and the tube should be flushed with 20 mL potable water (both the gastric 
and jejunal port).
The timing (time of day, interval) of dosing and specific instructions to subjects about 
when or how to take the dose will be supplied to the subject.  No restrictions are given 
with relation to the time of LCIG dosing relative to meals.
Initial Dose Titration
The initial infusion will be based on calculations described in this section.  Extra doses of 
LCIG may be administered to address immediate medical need throughout the day during 
initial titration and should be carefully recorded on the Dose Titration Diary.
The daily LCIG infusion dose may be adjusted based on the subject's response to the 
previous day's treatment and the amount of, if any of extra LCIG doses required.  If both 
the Investigator and subject are satisfied with the effectiveness of treatment, then no 
change in the LCIG infusion dose is required.  If clinically indicated, changes in the dose 
either upward or downward can be made to further optimize the subject's treatment 
response.
If at any time during titration the subject develops severe dyskinesia or other 
levodopa-related complications, the LCIG infusion can be paused, if judged absolutely 
necessary by the Investigator, until symptoms improve to a clinically acceptable level.
Additionally, if at any time during titration, the subject develops a prolonged "Off" state 
that is unsafe or causes the subject unacceptable discomfort, rescue oral LC-IR dose can 
be administered, if judged necessary by the Investigator, until symptoms improve.58
The continuous dose of LCIG should be adjusted to obtain the optimal clinical response 
for the individual subject.  Optimal clinical response is defined by maximizing the 


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functional "On" time and minimizing the number of "Off" episodes during the day.  This 
optimization also minimizes "On" time with troublesome dyskinesia.  This determination
is made by the Investigator.  
LCIG Infusion
LCIG concentration = 1 mL LCIG contains 20 mg of levodopa and 5 mg carbidopa 
(20 mg/mL).
Morning Dose
A morning dose will be administered as a bolus infusion by the pump to rapidly achieve a 
therapeutic dose level (over approximately 10 to 30 minutes).  This morning dose is 
generally 5 to 10 mL and corresponds to 100 to 200 mg of levodopa.
The total morning dose typically does not exceed 15 mL (300 mg levodopa).  Subjects are 
not administered a full equivalent of their usual oral morning dose of levodopa-carbidopa.  
Continuous Maintenance Dose
The Maintenance Dose is adjustable in steps of 2 mg/hour (0.1 mL/hour).  The dose 
should be calculated according to the subject's previous daily intake of levodopa.  The 
continuous maintenance dose is adjusted individually.  It is usually kept at 2 to 6 mL/hour 
(40 to 120 mg levodopa/hour).  However, higher doses may be clinically indicated.  
During the titration period, the continuous dose can be titrated in a step wise fashion that 
meets the clinical and medical needs of the subject.  The continuous maintenance dose is 
first calculated based on the subject's usual total daily dose minus the morning dose.  
During treatment, pump alarms may indicate kinking or knotting of the tube.  
Additionally there may be a sudden deterioration in treatment response with recurring 
motor fluctuations due to 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.


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If a problem develops with the LCIG system and the LCIG infusion needs to be 
temporarily discontinued, the Investigator should then place the subject on a regimen of 
oral levodopa-IR tablets until the problem is resolved and the LCIG infusion can be 
resumed the following morning.  If the subject is placed on an oral regimen of levodopa 
IR tablets; the dose prescribed should be based on the dose the subject was receiving just 
prior to the LCIG infusion interruption and adjust the dose as clinically indicated to 
stabilize the subject.  
Extra LCIG Doses
During initial titration, extra doses may be administered on an hourly basis at the 
Investigator's discretion based on the subject's response.  Subsequently, subjects will be 
allowed to self-administer additional extra doses of LCIG (at intervals of no less than 
2 hours) 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.  If the need for extra doses exceeds 5 times per day, the subject should be 
instructed to contact the Investigator. The Investigator should then consider the need to 
increase the subject's continuous daily maintenance infusion dose.  After the initial dose 
setting, fine adjustments of the morning dose, the maintenance dose and extra doses can 
be made as needed.  
Nasojejunal Tube
LCIG is intended for continuous intestinal administration.  A temporary nasojejunal tube 
may be used initially with the infusion pump to determine if the subject responds 
favorably to this method of treatment and to optimize the dose of LCIG before treatment 
with a permanent PEG-J tube is started.  Only the NJ sets available through this clinical 
study should be used with LCIG.  The NJ should be inserted by a gastroenterologist 
proceduralist, surgeon or interventional radiologist.  NJ may also be inserted by the 
passive method.
Following the placement of the NJ it will be necessary to perform a radiological check for 
proper tube placement before initiating LCIG. If NJ is placed via the passive method, the 


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radiological check will be completed when the tube is expected to be located in the correct 
position (which may take around 48 hours and local practice procedures should be 
followed).
Alternatively, subjects may proceed directly to placement of the permanent PEG-J tube 
and start titration without the NJ test phase if deemed appropriate by the Investigator. 
Percutaneous Endoscopic Gastrostomy with Jejunal Extension (PEG-J)
LCIG will be administered via the components of the percutaneous endoscopic 
gastrostomy – with jejunal extension (PEG-J) set.  Only the PEG-J sets available through 
this clinical study should be used with LCIG.
A thorough evaluation of the subject's risk of undergoing the PEG-J procedure will be 
performed by the Investigator and study gastroenterologist proceduralist or surgeon as 
part of the verification of Inclusion/Exclusion criteria prior to Screen V2.  Subjects 
deemed unsuitable for the PEG-J procedure will not be enrolled in the study.
The study gastroenterologist proceduralist, surgeon or qualified radiologist must take 
appropriate steps to evaluate and minimize the risk to subjects undergoing the PEG-J 
procedure including aftercare.  Additional evaluations for safety, other than those required 
by the protocol, are permitted at the Investigator's or Study GIs discretion (i.e., additional 
lab tests).
Placement of the PEG-J will be performed by a qualified gastroenterologist proceduralist, 
surgeon or qualified radiologist experienced with the placement of PEG-J tubes.  Each 
study site should have one study designated gastroenterologist proceduralist, surgeon, or 
qualified radiologist and one backup who has experience with and a thorough knowledge 
of endoscopy and PEG placement, aspects of PD and neurological patients, placement and 
maintenance of PEG-J tubes, the LCIG System and any related procedures.  They must 
also participate in study staff guided training or equivalent.


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The placement target for the end of the jejunal extension tubing is in the proximal small 
intestine past the ligament of Treitz.  Study site personnel will be trained with regard to 
the proper care and maintenance of the LCIG Infusion System to ensure that high quality 
care is provided to each subject.
The use of prophylactic antibiotics is required prior to PEG-J procedure.  At minimum, a 
single dose of a 1st or 3rd generation cephalosporin (or an antibiotic with similar coverage) 
must be administered approximately 30 minutes prior to the PEG-J procedure.
Following PEG-J placement and, at the discretion of the Investigator, the subject may 
begin initiation and titration of LCIG infusion.  LCIG initiation and titration will be 
performed in the hospital but may be continued as an outpatient (e.g., at a study site, 
titration center) with appropriate medical supervision.  The Sponsor will ensure the 
Investigator and site personnel are trained on LCIG initiation and titration.
The gastric port of the PEG-J should not be used for the delivery of nutrition and/or other 
medications unless judged medically necessary following consultation with the study 
designated physician.  If determined medically necessary, it is imperative that nutrition 
and/or other medications are delivered only through the gastric port and not the jejunal 
port.  The gastric port must be properly flushed and maintained as outlined in the provided 
aftercare procedure instructions for the PEG-J set.
Following the PEG-J placement procedure, aftercare of the PEG-J system will initially be 
performed by trained study staff.  Instruction and confirmation that the subject and/or 
care-partner have a good understanding of proper stoma aftercare and check of the stoma 
is required before discharge.  To ensure adequate adaptation of the stomach and 
abdominal walls and to reduce PEG-J infections, the aftercare procedure instructions 
provided by the Sponsor must be utilized.  During aftercare procedures, it is very 
important not to turn, rotate or twist the jejunal extension tube.
The gastroenterologist proceduralist, surgeon, or qualified radiologist, or their designated 
qualified personnel will examine the subject's stoma site between Study Day 2 and Study 


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Day 7 after PEG-J placement, and will continue to follow the subject's progress as an 
outpatient.  The gastroenterologist proceduralist/surgeon will continue to follow the 
subject's progress as an outpatient.
5.5.2
Identity of Investigational Product
The chemical nomenclature for levodopa is (-)-3-(3, 4-dihydroxyphenyl)-L-alanine.  The 
chemical name for carbidopa is (-)-L-α-h-ydrazino-3, 4-dihydroxy-α-
methylhydrocinnamic acid monohydrate.  Levodopa-carbidopa intestinal gel for 
upper-intestinal infusion is a suspension of levodopa-carbidopa monohydrate (4:1) in an 
aqueous gel (carboxymethylcellulose).
5.5.2.1
Investigational Product and Supplies
Table 5.
Study Drug
Study Drug
Route of Administration
Manufacturer
100 mL Levodopa (20 mg/mL)-carbidopa
monohydrate (5 mg/mL) intestinal gel 
medication cassette reservoirs
upper-intestinal infusion
Fresenius Kabi for AbbVie
Devices are listed below but are not limited to them alone.
Table 6.
Investigational Devices Provided for Delivery of Drug
Devices in LCIG System
Description
Manufacturer
Pump CADD Legacy 1400
Smiths Medical
NJ Tube
AbbVie or Covidien
Safety Adapter
Vygon
Extension Tube FR
Vygon
PEG Tube
AbbVie
Intestinal Tube
AbbVie
Y-Adapter for PEG Tube
AbbVie
Click Adapter for PEG Tube
AbbVie


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The Pump comes in a kit form that includes a holster, 2 batteries and an instruction 
booklet.  Should the holster get damaged due to wear and tear, an additional pump bag 
and/or holster can be provided to the subject.
AbbVie will provide LCIG, devices and ancillaries to the site to initiate LCIG after NJ 
and/or PEG-J placement.  
Any replacement LCIG pumps will be shipped to the Investigator allowing the 
Investigator to program and dispense the pump directly to the subject.
5.5.2.2
Packaging and Labeling
The medication will be packaged in accordance with the applicable local and federal 
regulations and Good Manufacturing Practices (GMP).
LCIG
Seven (7) medication cassette reservoirs of LCIG will be contained in an outer carton and 
this will comprise one kit.  The medication cassette reservoirs of LCIG and the carton will 
be labeled with all information as required by local regulations.  All labels must remain 
affixed to the primary and secondary packaging material.
5.5.2.3
Storage and Disposition of Study Drug
LCIG Storage
At the LCIG distribution depot, the cassettes with the LCIG suspension can be stored in 
the freezer (between –15°C and –25°C) for up to 2 years.  After thawing, the LCIG 
suspension can be stored in a refrigerator (between 2°C and 8°C) for up to 15 weeks.  
Thawed LCIG suspension should not be re-frozen.  The cassettes should be kept in the 
outer carton in order to protect from light.  An LCIG cassette medication should be used 
within 16 hours after removal from the refrigerator.  Once an LCIG cassette has been 
disconnected from the pump, it may not be reused at a later time.


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All study site clinical drug supplies are to be stored in a secure, limited-access area in 
accordance with labeled storage conditions.  The Investigator (or an authorized 
representative) will maintain accurate records of the disposition of clinical drug supplies 
received at the site.  These records shall include the amounts of drug supplies and the 
dates on which drug supplies were received from the drug depot, dispensed to the subject 
(by the site), returned by the subject and returned to the study site (devices) (LCIG 
cassettes).  If errors or damages in the clinical drug supply shipments occur, the 
Investigator and subsequently, the subject, will be instructed to contact the study site 
immediately.
5.5.3
Method of Assigning Subjects to Treatment Groups
Before the site is initiated, contact information and user guidelines for the IRT system will 
be provided to each site.  Upon receipt of study drug, the site will acknowledge receipt in 
the IRT system.
At Screening during Visit 1, each subject will be assigned a unique 5-digit number by the 
IRT system.  Following Visit 3, the site will contact the IRT to randomize the subject to 
OMT or LCIG.  Subjects randomized to OMT will continue on their current anti-PD 
medication regimen for the duration of the study.  For subjects randomized to LCIG, the 
site will obtain the study drug kit numbers to dispense at the designated Visits.  Study 
drug must not be dispensed without contacting the IRT.  Study drug may only be 
dispensed to subjects randomized to LCIG in the study through the IRT.
This is an open-label study and all eligible subjects will receive OMT or LCIG.
5.5.4
Selection and Timing of Dose for Each Subject
LCIG subject dosing will be individually optimized.  Subject dosing will be titrated 
following either NJ placement or the PEG-J procedure.  Dose adjustments can be made 
throughout the course of the study as clinically indicated.  The LCIG infusion is expected 
to infuse over approximately 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.


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While the subject is titrated, the study staff should complete Dose Titration Diary hourly 
until the dose is optimized and then recording whenever the dosage is adjusted or the 
subject received extra or if required rescue doses.
5.5.5
Blinding
This is an open-label study.  All eligible subjects will be randomized in a 1:1 ratio to 
receive OMT:LCIG.
Blinded centralized raters will be used to administer the NMSS and PDSS-2, the primary 
efficacy endpoints for this study, during Randomization at Visit 3 and Treatment Period 
visits.  Randomization, V3 will serve as the baseline for clinical assessment.  The scales 
will also be performed at Visits 6, 12, and 26.  The scales are to be performed by a trained 
blinded central rater who will not have access to the results of other study assessments or 
medical records for the subject and who will not participate in the care or management of 
the subject.  Each rating is based exclusively on an interview with the subject (and the 
subject's caregiver when available).
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense LCIG study drug only to subjects enrolled in the study and 
randomized to LCIG treatment in accordance with the protocol.  The study drug must not 
be used for reasons other than that described in the protocol.  The site will review LCIG 
cassette usage at drug resupply visits and assess compliance at each visit.  
5.5.7
Drug Accountability
Initial study supplies and 6 weeks of LCIG cassettes will be supplied to the Investigator 
by the drug depot.  It is at the discretion of AbbVie and/or the Investigator to discontinue 
subjects from the study who fail to take and/or return the appropriate amount of study 
drug.
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LCIG therapeutic systems are received intact and in the correct amounts.  This will be
documented by the Investigator signing and dating the Proof of Receipt (POR) after 
he/she receives LCIG from the depot for the initial supplies, and by signing the POR upon 
receipt of LCIG from the depot.  A current (running) and accurate inventory will be kept 
by the Investigator or the designated representatives in the IRT system, and will include 
shipping invoices and the date on which study drug was dispensed to the subject.  The 
IRT must be contacted when any subject discontinues the study.  The IRT will maintain a 
current and accurate inventory of all LCIG supplies, accountability, reconciliation, and 
returns for each site.  The investigational site and depot will also maintain current and 
accurate documentation of study drug details (i.e., kit number, number of used and unused 
cassettes) in the source document for each subject.  Returned study drug cassettes will be 
retained by the depot until returned for destruction.
An overall accountability of LCIG will be performed and verified by the Sponsor and the 
depot throughout the study.  All original LCIG cassettes (empty or containing unused 
LCIG) will be returned to the depot, according to instructions from AbbVie and according 
to local regulations.  Labels must remain attached to the containers.
Non-investigational medicinal product (standard of care) (e.g., generic name or brand 
name) must be obtained commercially.
5.5.8
Device Accountability
All pumps dispensed and returned and all tubes placed and removed will be tracked in the 
IRT and EDC system on the appropriate eCRF.  All devices must be accounted for 
throughout the study by the site.  All pumps, tubes, and accessories dispensed and 
returned and all tubes placed and removed will be tracked in the IRT and EDC system on 
the appropriate eCRF.  All devices must be accounted for throughout the study by the site.


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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is an open label study and all subjects will receive OMT or LCIG in an open-label 
fashion.
An open-label study design is appropriate for the following reasons:
1.
LCIG is an approved product with demonstrated efficacy
2.
Advanced PD is an orphan populations with a limited patient population available 
for recruitment
3.
An open-label design ensures that subjects randomized to optimized medical 
therapy do not have to undergo the invasive NJ and PEG-J procedure unnecessarily
4.
NJ testing period is not possible in a blinded study
5.
Per the Package Leaflet, Duodopa is initiated as monotherapy – tapering off of all 
other anti-PD medications besides levodopa at initiation would not be plausible in a 
blinded study
6.
The majority of patients are on other anti-PD medications in addition to levodopa 
and those randomized to OMT, would not be able to be maintained on levodopa 
monotherapy for 28 days safely
As there are no approved medications which treat NMS as a whole, this optimized 
medical therapy population is considered appropriate as a comparison group.
5.6.2
Appropriateness of Measurements
The NMSS was developed to evaluate the severity of individual non-motor symptoms in a 
patient with Parkinson's disease and to monitor the effect of an intervention on non-motor 
symptoms.
The PDSS-2 was developed to assess the profile of nocturnal disturbances in PD patients. 


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The UPDRS and PDQ-8 are currently accepted and validated methods of evaluating 
subjects with PD.  All safety assessments are standard measures used in pharmaceutical 
research.48,61,62
5.6.3
Suitability of Subject Population
Levodopa-responsive Parkinson's disease patients with severe motor fluctuations and 
hyperkinesia/dyskinesia when available combinations of Parkinson medicinal products 
have not given satisfactory results are eligible to participate.63
5.6.4
Selection of Doses in the Study
Subject dosing is determined individually.  Prior to subject enrollment, all anti-PD 
medications have been optimized and stabilized during the Screening Period.  For subjects 
randomized to LCIG, the starting dose of the infusion after placement of the NJ and/or 
PEG-J tube will be based on the daily dose of the oral levodopa prior to or at the time of 
study entry.  Subject dosing will be individually optimized.
The total dose/day of LCIG is composed of three individually adjusted doses:  (i) the 
morning dose, (ii) the continuous maintenance dose and (iii) extra doses.  The needs of 
individual subjects may vary depending on their particular condition and calculation of 
necessary dosing will be individualized based.  The LCIG infusion is expected to infuse 
over approximately 16 hours each day with a rate of infusion within the range of 1 to 
10 mL/hour (20 to 200 mg of levodopa/hour) in most instances.  The maximum LCIG 
dose administered in this study should not exceed 200 mg of levodopa/hour for 26 weeks.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this trial contains both: 


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●
An active pharmacological agent
●
Device component(s) (cassette, tubing, pump, connectors, etc.).
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug or 
the study device components, the investigator will provide an Other cause of the event.  
For adverse events to be considered intermittent, the events must be of similar nature and 
severity.  Adverse events, whether in response to a query, observed by site personnel, or 
reported spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.


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Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the Investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.  Also, fluctuating 
PD symptoms during titration should not be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
A hospitalization prior to the first screening visit (SV1), allowing the subject to arrive at 
the clinic in the "Off" state, will not be regarded as an SAE.  If not associated with 
worsening of Parkinson's disease symptoms, a hospitalization for dose adjustments of 
LCIG will not be regarded as a SAE.  A hospitalization because of a Product Complaint, 
such as a device dislocation without AE (i.e., without health impairment) will not be 
regarded as an SAE.
Hospitalization for scheduled tube placement/replacement should not be considered an 
SAE.


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Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.


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6.1.1.3
Adverse Events of Special Interest
Adverse events of special interest (AESI) are:
●
Gastrointestinal and gastrointestinal procedure related events
●
Polyneuropathy
●
Weight loss
For AESIs, serious and nonserious, meeting pre-defined criteria, specific questionnaires 
will be used to standardize the collection of follow-up information.  The AESI 
questionnaires are either sent to the site after Sponsor review or issued within the 
Electronic Data Capture (EDC) system once applicable.  The Investigator will email the 
completed questionnaires to the AbbVie Neuroscience Safety Management Team or enter 
the information into the EDC system once applicable.  If a subject develops signs and 
symptoms of polyneuropathy a standard panel of examinations will be suggested to the 
Investigator and certain laboratory tests (specified in questionnaire) will be required by 
the Sponsor.  The Investigator may perform additional other assessments that are deemed 
appropriate for further evaluation of polyneuropathy symptoms based on the presentation 
of the individual subject.  If weight loss is considered to be clinically significant, 
preventative measures will be taken to counteract weight loss.
For all AESIs, if the event meets seriousness criteria, the Investigator will report the event 
to the Sponsor within 24 hours of the site being made aware of the event according to 
Section 6.1.5.
Neuroscience Clinical Safety Management Team
AbbVie
1 North Waukegan Road
North Chicago, IL  60064-6075
Telephone Contact Information:
Office:
Fax:
Email:


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6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts 
the subject's usual activities.
Severe
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or 
life-threatening.
6.1.3
Relationship to Study Drug
For the assessment of drug event relationship, LCIG should be considered a therapeutic 
system consisting of drug, devices and placement procedure.  Causality assessments are 
always made over the system as a whole.
For the assessment of drug event relationship, those randomized to OMT should evaluate 
relatedness to any of the subject's anti-PD medication.
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship. 
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship. 


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For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, if the Investigator has not reported causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the Investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
Protocol-related nonserious adverse events that occur after signing the informed consent, 
prior to the start of study drug administration, will be collected.  All adverse events 
reported from the time of randomization until 30 days following last OMT dose, last study 
visit, discontinuation of study drug administration, removal of the PEG-J tube or Last 
LCIG Commercial Transition Visit have elapsed will be collected, whether solicited or 
spontaneously reported by the subject.  In addition, serious adverse events and protocol 
related non serious adverse events will be collected from the time the subject signed the 
study-specific informed consent.
Adverse event information will be collected as shown in Figure 3.


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Figure 3.
Adverse Event Collection
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) RAVE® system.  Serious adverse events that occur prior to 
the site having access to the RAVE® system, or if RAVE is not operable should be 
documented on the SAE Non-CRF forms and emailed (preferred route) or faxed to 
Clinical Pharmacovigilance within 24 hours of being made aware of the serious adverse 
event.
FAX to:
Email:




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The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 


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event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product and/or device must be reported 
to the Sponsor within 24 hours of the study site's knowledge of the event via the eCRF or 
Product Complaint form if eCRF is unavailable.  Product Complaints occurring during the 
study will be followed-up to a satisfactory conclusion.  All follow-up information is to be 
reported to the Sponsor (or an authorized representative) and documented in source as 
required by the Sponsor.  Product Complaints associated with adverse events will be 
reported in the study summary.  All other complaints will be monitored on an ongoing 
basis.
Product Complaints may require return of the product with the alleged complaint 
condition (cassette, pump, tubing, etc.).  In instances where a return is requested, every 
effort should be made by the investigator to return the product within 30 days.  If returns 
cannot be accommodated within 30 days, the site will need to provide justification and an 
estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
The Investigator should not implement any deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects.  When a deviation from the 




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treatment.  The treatment period will end on the day of the final visit for subjects 
randomized to OMT, and on the last day of LCIG study drug infusion for subjects 
randomized to LCIG treatment.
The last assessment prior to randomization will be considered baseline and the last 
assessment that is no more than 2 days after the end of the treatment period will be 
considered the final evaluation.
Safety Dataset
The safety analyses will be performed on the safety dataset which will include all subjects 
who are randomized to the optimized medical treatment, and all subjects who are 
randomized to LCIG and have study device (NJ and/or PEG-J) placement.  For 
assessments of safety, the treatment period will begin the day after randomization for 
subjects randomized to optimized medical treatment, and the day of NJ placement (or 
PEG-J placement if no NJ) for subjects randomized to LCIG.  The treatment period will 
end on the day of the final visit for subjects randomized to optimized treatment, and on 
the last day of LCIG infusion or device removal (whichever is later) in the study for 
subjects randomized to LCIG.  The last assessment prior to randomization will be 
considered baseline and the last assessment that is no more than 2 days after the end of the 
treatment period will be considered the final evaluation.
8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition, and Concomitant Medication
Demographic and Other Baseline Characteristics
All demographic variables will be summarized for the safety dataset unless otherwise 
specified.
For continuous demographic variables, including age, weight, height and body mass index 
(BMI), descriptive statistics (number of subjects with non-missing data, mean, standard 
deviation, median, minimum, and maximum) will be provided for each treatment group, 


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and for both treatment groups combined.  Overall treatment group differences will be 
tested using one-way ANOVA.
For categorical demographic variables, including gender and race, the number and 
percentage of subjects in each category will be provided for each treatment group, and for 
all treatment groups combined.  Overall treatment group comparability will be tested 
using Fisher's exact test.
For the ITT data set, baseline NMSS total score and PDSS-2 total score will be 
summarized.  One-way ANOVA will be used to assess the comparability of treatment 
groups.
Medical History
Medical history data will be summarized for the safety dataset using body systems and 
conditions/diagnoses as captured on the eCRF.  Parkinson's disease history will also be 
summarized.
Subject Disposition
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment group and for all treatment groups combined for the safety 
dataset.
The number and percentage of subjects who prematurely discontinue study will be 
summarized by treatment group and overall for the safety dataset for the primary reason 
as well as for all reasons collected.  In the summary, the number and percentage of 
subjects who discontinue due to any reason as well as due to each specific primary reason 
will be presented.  Subjects may report multiple reasons for prematurely discontinuing 
study, but the primary reason for discontinuation will be indicated in the eCRF and used 
to infer treatment group difference in subject's disposition.  The treatment group 
differences in the percentage of subjects who discontinued for any reason as well as for 
each specific reason will be assessed using Fisher's exact test.


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Previous and Concomitant Medications
Previous and concomitant medications will be coded by the most recent World Health 
Organization (WHO) Drug dictionary.  Previous and concomitant medications will be 
summarized by treatment group for the safety dataset.  No statistical testing will be 
performed.
8.1.3
Efficacy Analysis
All efficacy analyses will be performed on the ITT dataset unless otherwise specified.  
Comparisons between OMT and LCIG groups will be performed with two-sided tests at 
the significance level of 0.050.
Unless otherwise specified, the "baseline" for efficacy variables is defined as the last 
assessment taken on or before the day of randomization, and the "final observation" refers 
to the last non-missing observation in the Treatment Period (including evaluations 
conducted within 2 days after the last dose of study drug for subjects randomized to 
LCIG).
8.1.3.1
Primary Efficacy Analysis
There are 2 alternative primary efficacy variables, change from baseline to Week 26 for 
NMSS total score and change from baseline to Week 26 for PDSS-2 total score.  Either 
variable considered statistically significant after multiplicity adjustment is sufficient to 
declare success of the study.
NMSS Total Score
The NMSS was developed to assess non-motor symptoms in PD.  It is obtained through 
interview and rated by health professionals.  It contains 30 questions grouped into 
9 domains:  cardiovascular (2 items), sleep/fatigue (4 items), mood/cognition (6 items), 
perceptual problems/hallucinations (3 items), attention/memory (3 items), gastrointestinal 
tract (3 items), urinary (3 items), sexual function (2 items), and miscellaneous (4 items).  
Each question is scored with respect to severity and frequency.  Severity is rated on a 


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scale where 0 = none, 1 = mild, 2 = moderate and 3 = severe.  Frequency is rated on a 
scale where 1 = rarely, 2 = often, 3 = frequent and 4 = very frequent.  Item scores are 
calculated as the product of severity and frequency.  Domain scores and a total score are 
obtained by summing the item scores.
PDSS-2 Total Score
The PDSS-2 was developed from the PDSS based upon the need for a 
treatment-measuring tool containing PD-specific sleep disorders.  The instrument was 
extended to address specific sleep disturbances such as RLS, akinesia, pain, and sleep 
apnea.  The frequency is assessed for the 15 sleep problems based on a 5-point Likert-type 
scale (ranging from 0 [never] to 4 [very often]).  Scores are calculated for each domain as 
well as a total score.
Primary Analysis Model and Multiplicity Adjustment
The primary efficacy analysis model is a likelihood-based mixed-effects model repeated 
measures (MMRM) analysis of the change from baseline for each post-baseline 
observation using all observed data.  The model will include fixed, categorical effects for 
treatment, country, visit, and treatment-by-visit interaction, with continuous fixed 
covariates for baseline score and the baseline score-by-visit interaction.  The primary 
comparison will be the contrast between LCIG and optimized oral treatment at the 
Week 26 Visit.
The two-sided P values obtained from the MMRM model for NMSS total score change 
from baseline to Week 26 and PDSS-2 total score change from baseline to Week 26 will 
be adjusted for multiplicity using the Hochberg procedure.  This method controls the 
family-wise error rate (FWER) at a pre-specified significance level (alpha = 0.05).  
Specifically, the following steps will be followed:
●
If the larger of the 2 P values is ≤ 0.05 (i.e., both P values are ≤ 0.05), both 
endpoints are considered statistically significant.


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●
If the larger of the 2 P value is > 0.05, then compare the smaller P value with 
0.025.  The second endpoint is statistically significant if the P value is ≤ 0.025; 
otherwise, neither endpoint is considered statistically significant.
8.1.3.2
Secondary Efficacy Analysis
Secondary Analysis of the Primary Efficacy Variables
ANCOVA analyses will be carried out on change from baseline to final NMSS total score 
and change from baseline to final PDSS-2 total score.  The ANCOVA model will contain 
treatment and country as the main effects and baseline score as the covariate.
Sensitivity analyses will be carried out on the above variables with the same ANCOVA 
model using all randomized subjects.  In this analysis, Baseline Observation Carried 
Forward (BOCF) will be applied to subjects who do not have post-randomization 
assessment of NMSS or PDSS-2.
Key Secondary Efficacy Variables
Key secondary endpoints will consist of the following validated scales:
●
UPDRS Part II score
●
CGI-C
●
PDQ-8 summary index
The 3 key secondary variables will be analyzed with the same MMRM model as the 
primary analysis.  For the analysis on CGI-C, the scores collected at the visits will be the 
dependent variable.
If both primary efficacy variables are statistically significant after adjusting for 
multiplicity, the Stepwise Gatekeeping Procedure will be utilized and the 3 key secondary 
endpoints will be tested using the Hochberg procedure with significance level of 0.05.


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Other Secondary Efficacy Variables
Other secondary endpoints include:
●
NMSS domain scores
●
PDSS-2 domain scores
●
UPDRS total score, Part I score, Part III score, Part IV score
●
Parkinson Anxiety Scale (PAS) total and subscale scores
●
King's PD Pain Scale total and domain scores
These variables will be analyzed with the same MMRM model as the primary analysis.  
For the analysis on PGIC, the scores collected at the visits will be the dependent variable.
8.1.4
Safety Analysis
All safety analysis will be performed on the safety dataset unless otherwise specified.  
Comparisons between LCIG and OMT groups will be performed with two-sided test at 
the significance level of 0.05.
Unless otherwise specified, the treatment group differences in continuous safety variables 
(e.g., change from baseline to final observation on laboratory tests) will be assessed using 
an ANOVA model with the term of treatment, and the treatment group differences in 
binary safety variables will be evaluated using a Fisher's exact test.
8.1.4.1
OMT and LCIG Study Drug Exposure
The duration of OMT exposure will be calculated for each subject as the date of the last 
visit minus the date of randomization.  The duration of LCIG study drug exposure will be 
calculated for each subject as the date of the last dose of LCIG study drug minus the date 
of the first dose of LCIG study drug plus 1.  The duration of OMT and LCIG study drug 
exposure will be summarized with descriptive statistics (number of subjects with 
non-missing data, mean, standard deviation, median, minimum and maximum).


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8.1.4.2
Adverse Events
Adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Adverse events will be summarized by primary 
MedDRA system organ class (SOC) and preferred term (PT).  Subjects reporting more 
than one adverse event for a given MedDRA PT will be counted only once for that term.  
Subjects reporting more than one adverse event within an SOC will be counted only once 
for the SOC total.  Subjects reporting more than one adverse event will be counted only 
once in the overall adverse event total.
Each adverse event will be categorized by severity (mild, moderate, severe) and by 
relationship to study treatment (reasonable possibility, or no reasonable possibility).  
Detailed search criteria for adverse events of special interest (AESIs) will be defined in a 
SAP prior to database lock.
A treatment-emergent adverse event (TEAE) is defined as:
●
For OMT group:  any adverse event that begins or worsens in severity the day 
after randomization and within 30 days following the last visit.
●
For the LCIG group:  any adverse event that begins or worsens in severity 
from the day of the initial device placement (NJ or PEG-J)  through Week 26 
Visit for those subjects continuing to LCIG commercial treatment, or through 
30 days after final device removal for those subjects not continuing LCIG 
commercial treatment.
A summary of the number and percentage of subjects will be prepared for the following:
●
TEAEs
●
TE Serious AEs (including deaths)
●
TEAEs leading to premature discontinuation of treatment
●
TEAEs by maximum relationship to study drug
●
TEAEs by maximum severity
●
Treatment-emergent AESIs


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Serious adverse events with onset during the Screening Period for all subjects screened, 
adverse events and serious adverse events with onset after day of randomization and 
before day of initial device placement for the LCIG group, as well as adverse events 
during the transition period for LCIG subjects continuing LCIG commercial treatment 
will also be summarized.
8.1.4.3
Clinical Laboratory Variables
For each continuous clinical laboratory variable, analyses of the mean change from 
baseline to each scheduled visit and to the minimum, maximum and final value will be 
presented by treatment group.
Clinical laboratory observations will be categorized as normal, low, or high relative to the 
reference (normal) range associated with the laboratory that performed the assay.  For 
each clinical laboratory variable with a reference range, shift tables will be prepared for 
reference range category shifts from baseline to minimum, maximum and final value.
Criteria for potentially clinically significant (PCS) values will be pre-specified for 
selected laboratory variables in an SAP prior to database lock.  For each variable, a 
summary of the number and percentage of subjects who have at least one post-baseline 
observation that meets the PCS criteria and is more extreme than their baseline value will 
be provided.
8.1.4.4
Vital Sign Variables and Weight
For each vital sign and weight variable, analyses of the mean change from baseline to 
each scheduled visit and to the final value will be presented by treatment group.  For this 
analysis, the average of multiple observations on the same day will be calculated and 
treated as the observation for the day.  For LCIG subjects' visits with multiple 
observations scheduled on the same day, the post-infusion change from the day's 
pre-infusion baseline will be summarized for each scheduled time point.


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Criteria for potentially clinically significant (PCS) values will be pre-specified for 
selected vital sign and weight variables prior to database lock.  For each variable, a 
summary of the number and percentage of subjects who have at least one post-baseline 
observation that meets the PCS criteria and is more extreme than their baseline value will 
be provided.
8.1.4.5
ECG Variables
For each ECG variable, analyses of the mean change from baseline to each scheduled visit 
and to the final value will be presented by treatment group.  For this analysis, the average 
of multiple observations on the same day will be calculated and treated as the observation 
for the day.  For LCIG subjects' visits with multiple observations scheduled on the same 
day, the post-infusion change from the day's pre-infusion baseline will be summarized for 
each scheduled time point.
Criteria for potentially clinically significant (PCS) values will be pre-specified for 
selected ECG variables prior to database lock.  For each variable, a summary of the 
number and percentage of subjects who have at least one post-baseline observation that 
meets the PCS criteria and is more extreme than their baseline value will be provided.
8.1.4.6
Additional Safety Variables
The following additional summaries of safety measures will be prepared.
●
The responses to the MIDI
●
The responses to the C-SSRS
●
The responses to the Sleep Attacks Questionnaire
●
Percent of subjects who are cognitive impaired (MoCA score ≤ 26)
8.1.5
Interim Analysis
No interim analysis is planned for this study.


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8.2
Determination of Sample Size
Approximately 88 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either optimized medical treatment or LCIG.  There are no results on NMSS or PDSS-2 
available from randomized trials comparing LCIG and OMT.  Interim data from ongoing 
Phase 3b Study M12-920 showed that the improvement in NMSS total score from 
baseline to Week 12 is 24.8 in the LCIG group with standard deviation of 24.  Results 
from Zibetti et al (2013) showed that the improvement in PDSS-2 total score after an 
average of 3.5 months of LCIG treatment was 13.1.  The standard deviation was not 
provided and is estimated to be 12.2 assuming the correlation between baseline and 
follow-up visits is 0.5.
The significance level for this study is 0.05.  For sample size determination, it is assumed 
that the improvement in the OMT group is 33% of the LCIG group, i.e., the improvement 
is 8.2 on NMSS total score and 4.3 on PDSS-2 total score, and that the correlation 
between these 2 measures is 0.5.  Simulation showed that a study with 37 subjects per 
group will have 90% power to declare statistical significance on at least one of these 2 
alternative primary endpoints after multiplicity adjustment using Hochberg procedure.  It 
is further assumed that 10% of randomized subjects in either treatment group will not 
provide post-randomization efficacy assessment.  Additional simulations showed that 44 
subjects per group will provide 90% power in the sensitivity analysis using baseline 
observation carried forward for subjects without post-randomization assessment.  
Therefore the total planned enrollment is decided to be 88 subjects.
8.3
Randomization Methods
Approximately 88 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either optimized medical treatment or LCIG at the end of Visit 3.  Subject randomization 
will be stratified by country.


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9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.


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9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
9.3.1
Informed Consent Form and Explanatory Material
The Principal Investigator will prepare the site-specific consent form and explanatory 
material required to obtain subject's consent to participate in the study with the 
cooperation of the Sponsor and will revise these documents as required.  The prepared or 
revised consent forms and explanatory material will be submitted to the Sponsor.  
Approval of the IRB/IEC will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
When important new information related to the subject's consent becomes available, the 
Principal Investigator will revise the consent form and explanatory material based on the 
information without delay and will obtain the approval of the IRB/IEC prior to use in the 
study.  The Investigator will provide the information, without delay, to each subject 
already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The Investigator shall also provide a further explanation using 


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the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.
If a subject has a Legally Authorized Representative (LAR), a revised informed consent 
shall be obtained from the LAR for subject's continued participation in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.


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The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Data from the NMSS and the PDSS-2 will be entered directly into the Rater Station by the 
Blinded Central Rater, and this will be the source for these data.  The Rater Station Client 
and Rater Station are provided by the vendor Bracket, Wayne, PA.  Bracket's databases 
and web portal are 21 CFR Part 11 compliant.  Rater Station client is software that is 
loaded onto a laptop device and Rater Station web is the secure central database to which 
all data from the client is uploaded.  Rater Station uses AES (Advanced Encryption 
Standard) encryption implementing a 256-bit encryption key.


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11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
12.1
Subject Privacy
All information concerning LCIG and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of LCIG.  
This information may be disclosed as deemed necessary by AbbVie to other Clinical 
Investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the Investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 
data/documents for trial-related monitoring, audits, IEC/IRB review and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for Levodopa-Carbidopa 
Intestinal Gel and for subjects randomized to OMT will review the product label 
for the subjects' respective OMT.
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.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
An Open-label, Randomized 26-Week Study Comparing 
Levodopa-Carbidopa INteStInal Gel (LCIG) THerapy to Optimized 
Medical Treatment (OMT) on Non-Motor Symptoms (NMS) in 
Subjects with Advanced Parkinson's Disease – INSIGHTS Study
Protocol Date:
31 May 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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:  a clinical and 
pharmacokinetic study.  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 chemical 
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.
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.


Levodopa-Carbidopa Intestinal Gel
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12.
Deuschl G, Schade-Brittinger C, Krack P, et al.  A randomized trial of deep-brain 
stimulation for Parkinson's disease.  N Engl J Med.  2006;355(9):896-908.
13.
Weaver F, Follett K, Stern M, et al.  Bilateral deep brain stimulation vs best 
medical therapy for patients with advanced Parkinson disease:  a randomized 
controlled trial.  JAMA.  2009;301(1):63-73.
14.
Hariz MI.  Complications of deep brain stimulation surgery.  Mov Disord.  
2002;17 (Suppl 3):S162-6.
15.
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.
16.
Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, et al; NMSS Validation 
Group.  The impact of non-motor symptoms on health-related quality of life of 
patients with Parkinson's disease.  Mov Disord.  2011;26(3):399-406.
17.
Honig H, Antonini A, Martinez-Martin P, et al.  Intrajejunal levodopa infusion in 
Parkinson's disease:  a pilot multicenter study of effects on non-motor symptoms 
and quality of life.  Mov Disord.  2009;24(10):1468-74.
18.
Barone P, Antonini A, Colosimo C, et al; PRIAMO study group.  The PRIAMO 
study:  a multicenter assessment of non-motor symptoms and their impact on 
quality of life in Parkinson's disease.  Mov Disord.  2009;24(11):1641-9.
19.
Witjas T, Kaphan E, Azulay JP, et al.  Nonmotor fluctuations in Parkinson's 
disease:  frequent and disabling.  Neurology.  2002;59(3):408-13.
20.
Chaudhuri KR, Martinez-Martin P, Schapira AHV, et al.  International multicentre 
pilot study of the first comprehensive self-completed nonmotor symptoms 
questionnaire for Parkinson's disease:  the NMSQuest study.  Mov Disord.  
2006;21(7):916-23.
21.
Ondo WG, Dat Vuong K, Khan H, et al.  Daytime sleepiness and other sleep 
disorders in Parkinson's disease.  Neurology.  2001;57(8):1392-6.


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22.
Olanow CW, Antonini A, Kieburtz K, et al  Randomized, double-blind, 
double-dummy study of continuous infusion of levodopa-carbidopa intestinal gel in 
patients with advanced parkinson's disease:  efficacy and safety.  In:  Movement 
Disorder Society International Congress; June 17-21, 2012; Dublin, Ireland.  
Abstract 411.
23.
Westin J, Nyholm D, Groth T, et al.  Outcome prediction of enteral
levodopa/carbidopa infusion in advanced Parkinson's disease.  Parkinsonism Relat 
Disord.  2006;12(8):509-13.
24.
Kieburtz K, Antonini A, Olanow CL, et al.  Randomized, double-blind, 
double-dummy study of continuous infusion of levodopa-carbidopa intestinal gel in 
patients with advanced parkinson's disease:  functional and quality-of-life 
outcomes.  In:  Movement Disorder Society International Congress; 
June 17-21, 2012; Dublin, Ireland.  Abstract 385.
25.
Hinnel C, Hurt CS, Landau S, et al; PROMS-PD Study Group.  Nonmotor versus 
motor symptoms:  how much do they matter to health status in Parkinson's disease?  
Mov Disord.  2012;27(2):236-41.
26.
Parkinson J.  An essay on the shaking palsy.  1817.  J Neuropsychiatry Clin 
Neurosci.  2002;14(2):223-36.
27.
Shulman LM, Taback RL, Rabinstein AA, et al.  Non-recognition of depression 
and other non-motor symptoms in Parkinson's disease.  Parkinsonism Relat Disord.  
2002;8(3):193-7.
28.
Chaudhuri KR, Prieto-Jurcynska C, Naidu Y, et al.  The nondeclaration of 
nonmotor symptoms of Parkinson's disease to health care professionals:  an 
International study using the nonmotor symptoms questionnaire.  Mov Disord.  
2010;25(6):704-9.
29.
Honig H, Antonini A, Martinez-Martin P, et al.  Intrajejunal levodopa infusion in 
Parkinson's disease:  a pilot multicenter study of effects on nonmotor symptoms 
and quality of life.  Mov Disord.  2009;24(10):1468-74.


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30.
Fasano A, Ricciardi L, Lena F, et al.  Intrajejunal levodopa infusion in advanced 
Parkinson's disease:  long-term effects on motor and non-motor symptoms and 
impact on patient's and caregiver's quality of life.  Eur Rev Med Pharmacol Sci.  
2012;16(1):79-89.
31.
Reddy P, Martinez-Martin P, Rizos A, et al.  Intrajejunal levodopa versus 
conventional therapy in Parkinson disease: motor and nonmotor effects.  Clin 
Neuropharmacol  2012;35(5):205-7.
32.
Pursiainen V, Pekkonen E.  Intraduodenal levodopa infusion reduces non-motor 
symptoms in advanced Parkinson's disease.  Mov Disord.  2011;26 (Suppl 2):S296.
33.
Zibetti M, Rizzone M, Merola A, et al.  Sleep improvement with
levodopa/carbidopa intestinal gel infusion in Parkinson disease.  Acta Neurol 
Scand.  2013;127(5):e28-32.
34.
Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence.  
Non-motor symptoms of Parkinson's disease:  diagnosis and management.  Lancet 
Neurol.  2006;5(3):235-45.
35.
Terriff DL, Williams JV, Patten SB, et al.  Patterns of disability, care needs, and 
quality of life of people with Parkinson's disease in a general population sample.  
Parkinsonism Relat Disord.  2012;18(7):828-32.
36.
Hornykiewicz O.  The mechanisms of action of L-dopa in Parkinson's disease.  Life 
Sci.  1974;15(7):1249-59.
37.
de la Fuente-Fernández R, Lu JQ, Sossi V, et al.  Biochemical variations in the 
synaptic level of dopamine precede motor fluctuations in Parkinson's disease:  PET 
evidence of increased dopamine turnover.  Ann Neurol.  2001;49(3):298-303.
38.
Nyholm D, Lennernäs H, Gomes-Trolin C, et al.  Levodopa pharmacokinetics and 
motor performance during activities of daily living in patients with Parkinson's 
disease on individual drug combinations.  Clin Neuropharmacol.  
2002;25(2):89-96.
39.
Rivera-Calimlim L, Dujovne CA, Morgan JP, et al.  Absorption and metabolism of 
L-dopa by the human stomach.  Eur J Clin Invest.  1971;1(5):313-20.


Levodopa-Carbidopa Intestinal Gel
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40.
Olanow CW, Obeso JA, Stocchi F.  Continuous dopamine-receptor treatment of 
Parkinson's disease:  scientific rationale and clinical implications.  Lancet Neurol.  
2006;5(8):677-87.
41.
Nutt JG.  Pharmacokinetics and pharmacodynamics of levodopa.  Mov Disord.  
2008;23 (Suppl 3):S580-4.
42.
AbbVie.  Levodopa-Carbidopa Investigator's Brochure Edition 12.  07 April 2017.
43.
AbbVie.  Levodopa-Carbidopa Risk Management Plan Edition 5.  December 2011.
44.
Folstein SE, Folstein SE, McHugh PR.  "Mini-mental state."  A practical method 
for grading the cognitive state of patients for the clinician.  J Psychiatr Res.  
1975;12(3):189-98.
45.
Nasreddine ZS, Phillips NA, Bédirian V, et al.  The Montreal Cognitive 
Assessment, MOCA:  a brief screening tool for mild cognitive impairment.  J AM 
Geriatr Soc.  2005;53(4):695-9.
46.
Christenson GA, Faber JR, de Zwann M.  Compulsive buying:  descriptive 
characteristics and psychiatric comorbidity.  J Clin Psychiatry.  1994;55(1):5-11.
47.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs.columbia.edu/.
48.
Chaudhuri KR, Martinez-Martin P, Schapira AHV, et al.  The metric properties of 
a novel non-motor symptoms scale for Parkinson's disease:  results from an 
international pilot study.  Mov Disord.  2007;22(13):1901-11.
49.
Chaudhuri KR, Martinez-Martin P, Schapira AHV, et al.  International multicenter 
pilot study of the first comprehensive self-completed nonmotor symptoms 
questionnaire for Parkinson's disease:  the NMSQuest study.  Mov Disord.  
2006;21(7):916-23.
50.
Högl B, Arnulf I, Comella C, et al.  Scales to assess sleep impairment in 
Parkinson's disease:  critique and recommendations.  Mov Disord.  
2010;25(16):2704-16.


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51.
Trenkwalder C, Kohnen R, Högl B, et al.  Parkinson's disease sleep
scale--validation of the revised version PDSS-2.  Mov Disord.  2011;26(4):644-52.
52.
Martinez-Martin P, Gil-Nagel A, Gracia LM, et al.  Unified Parkinson's Disease 
Rating Scale characteristics and structure.  The Cooperative Multicentric Group.  
Mov Disord.  1994;9(1):76-83.
53.
Guy W. ECDEU Assessment Manual for Psychopharmacology – Revised.  
Rockville, MD.  US Department of Health, Education, and Welfare, Public Health 
Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research 
Programs.  1976.  p. 218-22.
54.
Jenkinson C, Fitzpatrick R, Peto V.  The Parkinson's Disease Questionnaire:  User 
Manual for the PDQ-39, PDQ-8 and the PDQ Summary Index.  Oxford:  Health 
Services Research Unit.  1998.
55.
Leentjens AF, Dujardin K, Pontone GM, et al.  The Parkinson Anxiety Scale 
(PAS):  development and validation of a new anxiety scale.  Mov Disord.  
2014;29(8):1035-43.
56.
Forjaz MJ, Ayala A, Martinez-Martin P, et al.  Is the Parkinson anxiety scale 
comparable across raters?  Mov Disord.  Epub 27 Dec 2014.
57.
Sheikh JI, Yesavage JA.  Geriatric Depression Scale (GDS):  recent evidence and 
development of a shorter version.  Clin Gerontologist.  1986;5(1-2):165-73.
58.
Weintrub D, Oehlberg KA, Katz IR, et al.  Test characteristics of the 15-item 
geriatric depression scale and Hamilton depression rating scale in Parkinson 
disease.  Am J of Geriatr Psychiatry.  2006;14(2):169-75.
59.
AbbVie.  Levodopa-Carbidopa PLR with annotations DN2489v2.  22 June 2012.
60.
Rizos AM, Martinez-Martin P, Pal S, et al.  Validation of a novel Parkinson's 
disease pain scale (King's PD pain scale):  a multicentre pilot study.  Poster 
presented at:  The 18th International Congress of Parkinson's Disease and 
Movement Disorders; June 8-12, 2014; Stockholm, Sweden.  Poster 510.


Levodopa-Carbidopa Intestinal Gel
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61.
Cools R.  Dopaminergic modulation of cognitive function-implications for 
L-DOPA treatment in Parkinson's disease.  Neurosci Biobehav Rev.  
2006;30(1):1-23.
62.
Tombaugh TN, Kozak J, Rees L.  Normative data stratified by age and education 
for two measures of verbal fluency:  FAS and animal naming.  Arch Clin 
Neuropsychol.  1999;14(2):167-77.
63.
Duodopa Intestinal Gel [Summary of Product Characteristics].  North Chicago, IL; 
AbbVie Inc., 2014.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Clinical
CDSM
Statistics


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Appendix C.
UK Parkinson's Disease Society Brain Bank Clinical Diagnostic 
Criteria
Step 1.  Diagnosis of Parkinsonian Syndrome
1.
Bradykinesia (slowness of initiation of voluntary movement with progressive 
reduction in speed and amplitude of repetitive actions).
2.
And at least one of the following:
a.
muscular rigidity
b.
4 – 6 Hz rest tremor
c.
postural instability not caused by primary visual, vestibular, cerebellar or 
proprioceptive dysfunction
Step 2.  Exclusion Criteria for Parkinson's Disease
1.
history of repeated strokes with stepwise progression of Parkinsonian features
2.
history of repeated head injury
3.
history of definite encephalitis
4.
oculogyric crises+
5.
neuroleptic treatment at onset of symptoms
6.
sustained remission
7.
more than 1 affected relative*
8.
strictly unilateral features after three years
9.
supranuclear gaze palsy
10.
cerebellar signs
11.
early severe autonomic involvement
12.
early severe dementia with disturbances of memory, language and praxis
13.
Babinski's sign


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14.
presence of a cerebral tumor or communicating hydrocephalus on CT scan
15.
negative response to large doses of levodopa (if malabsorption excluded)
16.
MPTP exposure
Step 3.  Supportive Prospective Positive Criteria for Parkinson's Disease
(Three or more required for diagnosis of definite Parkinson's disease)
1.
unilateral onset
2.
rest tremor present
3.
progressive disorder
4.
persistent asymmetry affecting the side of onset most
5.
excellent response (70 – 100%) to levodopa
6.
severe levodopa-induced chorea
7.
levodopa response for ≥ 5 years
8.
clinical course of ≥ 10 years
*
Refers only to 1st and 2nd degree relatives.
+
If present at the time of PD diagnosis.


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Appendix D.
Potentially Clinically Significant Laboratory Values for Study M12-927*
CTCAE v4.0 Term
PCS 
Value/Grade
PCS
Value
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Activated partial 
thromboplastin time 
prolonged (aPTT)
1
> ULN
> ULN – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN; hemorrhage
--
Hemoglobin decreased
2
< 10.0 g/dL
< LLN – 10.0 g/dL
< 10.0 – 8.0 g/dL
< 8.0 g/dL
Life-threatening 
consequences; urgent 
intervention indicated
< 6.2 mmol/L
< LLN – 6.2 mmol/L
< 6.2 – 4.9 mmol/L
< 4.9 mmol/L
< 100 g/L
< LLN – 100 g/L
< 100 – 80g/L
< 80 g/L; transfusion indicated
Hemoglobin increased
3
> 4 gm/dL above ULN
Increase in
> 0 – 2 gm/dL above 
ULN or above 
baseline if baseline is 
above ULN
Increase in
> 2 – 4 gm/dL above 
ULN or above 
baseline if baseline is 
above ULN
Increase in > 4 gm/dL above 
ULN or above baseline if 
baseline is above ULN
--
INR increased
1
> ULN
> 1 – 1.5 × ULN
> 1.5 – 2.5 × ULN
> 2.5 × ULN
--
> 1 – 1.5 times above 
baseline if on 
anticoagulation
> 1.5 – 2.5 times 
above baseline if on 
anticoagulation
> 2.5 times above baseline if 
on anticoagulation
Leukocytosis 
(WBC increased)
3
> 100,000/mm3
--
--
> 100,000/mm3
Clinical manifestations 
of leucostasis; urgent 
intervention indicated
Lymphocyte count 
decreased
3
< 500/mm3
< LLN – 800/mm3
< 800 – 500/mm3
< 500 – 200/mm3
< 200/mm3
< 0.5 × 109/L
< LLN – 0.8 × 109/L
< 0.8 – 0.5 × 109/L
< 0.5 – 0.2 × 109/L
< 0.2 × 109/L
Lymphocyte count 
increased
3
> 20,000/mm3
--
> 4000 – 20,000/mm3
> 20,000/mm3
--


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CTCAE v4.0 Term
PCS 
Value/Grade
PCS
Value
Grade 1
Grade 2
Grade 3
Grade 4
Hematology (continued)
Neutrophil count 
decreased
3
< 1000/mm3
< LLN – 1500/mm3
< 1500 – 1000/mm3
< 1000 – 500/mm3
< 500/mm3
< 1.0 × 109/L
< LLN – 1.5 × 109/L
< 1.5 – 1.0 × 109/L
< 1.0 – 0.5 × 109/L
< 0.5 × 109/L
Platelet count 
decreased
2
< 75,000/mm3
< LLN – 75,000/mm3
< 75,000 – 50,000/mm3
< 50,000 – 25,000/mm3
< 25,000/mm3
< 75.0 × 109/L
< LLN – 75.0 × 109/L
< 75.0 – 50.0 × 109/L
< 50.0 – 25.0 × 109/L
< 25.0 × 109/L
White blood cell 
decreased
3
< 2000/mm3
< LLN – 3000/mm3
< 3000 – 2000/mm3
< 2000 – 1000/mm3
< 1000/mm3
< 2.0 × 109/L
< LLN – 3.0 × 109/L
< 3.0 – 2.0 × 109/L
< 2.0 – 1.0 × 109/L
< 1.0 × 109/L
Chemistry
Blood bilirubin 
increased
2
> 1.5 × ULN
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 10.0 × ULN
> 10.0 × ULN
Cholesterol high
4
> 500 mg/dL
> ULN – 300 mg/dL
> 300 – 400 mg/dL
> 400 – 500 mg/dL
> 500 mg/dL
> 12.92 mmol/L
> ULN – 7.75 mmol/L
> 7.75 – 10.34 mmol/L
> 10.34 – 12.92 mmol/L
> 12.92 mmol/L
Creatinine increased
2
> 1.5 × ULN
> 1 – 1.5 × baseline
> 1.5 – 3.0 × baseline
> 3.0 baseline
> 6.0 × ULN
> ULN – 1.5 × ULN
> 1.5 – 3.0 × ULN
> 3.0 – 6.0 × ULN
GGT increased
2
> 2.5 × ULN
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
Corrected Serum Calcium of:
Hypercalcemia
3
> 12.5 mg/dL
> ULN – 11.5 mg/dL
> 11.5 – 12.5 mg/dL
> 12.5 – 13.5 mg/dL
> 13.5 mg/dL
> 3.1 mmol/L
> ULN – 2.9 mmol/L
> 2.9 – 3.1 mmol/L
> 3.1 – 3.4 mmol/L
> 3.4 mmol/L
Ionized Calcium
> 1.6 mmol/L
> ULN – 1.5 mmol/L
> 1.5 – 1.6 mmol/L; 
symptomatic
> 1.6 – 1.8 mmol/L; 
hospitalization indicated
> 1.8 mmol/L; 
life-threatening 
consequences


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CTCAE v4.0 Term
PCS 
Value/Grade
PCS
Value
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry (continued)
Fasting Glucose Value
Hyperglycemia
3
> 250 mg/dL
> ULN – 160 mg/dL
> 160 – 250 mg/dL
> 250 – 500 mg/dL
> 500 mg/dL
> 13.9 mmol/L
> ULN – 8.9 mmol/L
> 8.9 – 13.9 mmol/L
> 13.9 – 27.8 mmol/L; 
hospitalization indicated
> 27.8 mmol/L; 
life-threatening 
consequences
Hyperkalemia
3
> 6.0 mmol/L
> ULN – 5.5 mmol/L
> 5.5 – 6.0 mmol/L
> 6.0 – 7.0 mmol/L; 
hospitalization indicated
> 7.0 mmol/L; 
life-threatening 
consequences
Hypernatremia
3
> 155 mmol/L
> ULN – 150 mmol/L
> 150 – 155 mmol/L
> 155 – 160 mmol/L; 
hospitalization indicated
> 160 mmol/L; 
life-threatening 
consequences
Hypertriglyceridemia
3
> 500 mg/dL mg/dL
150 – 300 mg/dL
> 300 – 500 mg/dL
> 500 – 1000 mg/dL
> 1000 mg/dL
> 5.7 mmol/L
1.71 – 3.42 mmol/L
> 3.42 – 5.7 mmol/L
> 5.7 – 11.4 mmol/L
> 11.4 mmol/L; 
life-threatening 
consequences
Hyperuricemia
(Uric Acid Increased)
4
> 10 mg/dL
> ULN – 10 mg/dL 
(0.59 mmol/L) 
without physiologic 
consequences
--
> ULN – 10 mg/dL 
(0.59 mmol/L) with 
physiologic consequences
> 10 mg/dL
> 0.59 mmol/L
> 0.59 mmol/L; 
life-threatening 
consequences


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CTCAE v4.0 Term
PCS 
Value/Grade
PCS
Value
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry (continued)
Hypoalbuminemia
3
< 2 g/dL
< LLN – 3 g/dL
< 3 – 2 g/dL
< 2 g/dL
Life-threatening 
consequences; urgent 
intervention indicated
< 20 g/L
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
Corrected Serum Calcium
Hypocalcemia
3
< 7.0 mg/dL
< LLN – 8.0 mg/dL
< 8.0 – 7.0 mg/dL
< 7.0 – 6.0 mg/dL
< 6.0 mg/dL
< 1.75 mmol/L
< LLN – 2.0 mmol/L
< 2.0 – 1.75 mmol/L
< 1.75 – 1.5 mmol/L
< 1.5 mmol/L
Ionized Calcium
< 0.9 mmol/L
< LLN – 1.0 mmol/L
< 1.0 – 0.9 mmol/L; 
symptomatic
< 0.9 – 0.8 mmol/L; 
hospitalization indicated
< 0.8 mmol/L; 
life-threatening 
consequences
Hypoglycemia
3
< 40 mg/dL
< LLN – 55 mg/dL
< 55 – 40 mg/dL
< 40 – 30 mg/dL
< 30 mg/dL
< 2.2 mmol/L
< LLN – 3.0 mmol/L
< 3.0 – 2.2 mmol/L
< 2.2 – 1.7 mmol/L
< 1.7 mmol/L; 
life-threatening 
consequences; seizures
Hypokalemia
3
< 3.0 mmol/L
< LLN – 3.0 mmol/L
< LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
< 3.0 – 2.5 mmol/L; 
hospitalization indicated
< 2.5 mmol/L; 
life-threatening 
consequences
Hyponatremia
3
< 130 mmol/L
< LLN – 130 mmol/L
--
< 130 – 120 mmol/L
< 120 mmol/L; 
life-threatening 
consequences


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CTCAE v4.0 Term
PCS 
Value/Grade
PCS
Value
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry (continued)
Hypophosphatemia
3
< 2.0 mg/dL
< LLN – 2.5 mg/dL
< 2.5 – 2.0 mg/dL
< 2.0 – 1.0 mg/dL
< 1.0 mg/dL
< 0.6 mmol/L
< LLN – 0.8 mmol/L
< 0.8 – 0.6 mmol/L
< 0.6 – 0.3 mmol/L
< 0.3 mmol/L; 
life-threatening 
consequences
Enzymes
Alanine 
aminotransferase 
(ALT) increased
2
> 3 × ULN
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
Alkaline phosphatase 
increased
2
> 2.5 × ULN
> ULN – 2.5 × ULN
> 2.5 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
Aspartate 
aminotransferase (AST) 
increased
2
> 3 × ULN
> ULN – 3.0 × ULN
> 3.0 – 5.0 × ULN
> 5.0 – 20.0 × ULN
> 20.0 × ULN
CPK increased
3
> 5 × ULN
> ULN – 2.5 × ULN
> 2.5 × ULN – 5 × 
ULN
> 5 × ULN – 10 × ULN
> 10 × ULN
Adapted from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  May 28, 2009 (v4.03:  June 14, 2010)
*
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  May 28, 2009 (v4.03:  June 14, 2010).


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Appendix E.
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:," building number previously read:
Has been changed to read:
Section 1.2  Synopsis
Subsection Methodology:
Heading "LCIG Group:"
First paragraph, first sentence previously read:
In accordance with the LCIG approved Product Label for countries participating in the 
study, those subjects randomized to LCIG must discontinue all other anti-PD medications
(e.g., dopamine agonists, COMT-inhibitors, amantadine, MAO-B inhibitors, anti-
cholinergics, and subcutaneous apomorphine etc.) prior to LCIG initiation on Day 1 (V4); 
these medications should be tapered off according to their individual package insert and at 
the discretion of the Investigator.  
Has been changed to read:
In accordance with the LCIG approved Product Label for countries participating in the 
study, those subjects randomized to LCIG must discontinue all other anti-PD medications 
(e.g., dopamine agonists, COMT-inhibitors, amantadine, MAO-B inhibitors, anti-
cholinergics, and subcutaneous apomorphine etc.) prior to LCIG initiation on Day 1 (V4); 
these medications should be tapered off according to the prescribing information and the 
discretion of the Investigator.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "RSI" and "SOP"
RSI
Reference Standard Information
SOP
standard operating procedure
Section 3.2  Benefits and Risks
Subsection Risks
First paragraph, last sentence previously read:
These and additional information on risks are available in the SmPC or Product 
Monograph.42
Has been changed to read:
These and additional information on risks are available in the Investigator's Brochure.42
Section 5.1  Overall Study Design and Plan:  Description
First paragraph, last sentence previously read:
This study will be conducted at approximately 40 – 50 sites that specialize in movement 
disorders in approximately 10 countries where LCIG is available commercially.
Has been changed to read:
This study will be conducted at approximately 40 – 50 sites that specialize in movement 
disorders in approximately 10 countries.
Section 5.1.2.2  LCIG Treatment Group
Subsection Tapering of Anti-PD Medications Other Than Levodopa
First sentence previously read:
All subjects randomized to the LCIG group should have all anti-PD medications, with the 
exception of levodopa formulations, tapered off within 14 days after randomization in 
accordance with individual SmPCs at the discretion of the Investigator.  


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Has been changed to read:
All subjects randomized to the LCIG group should have all anti-PD medications, with the 
exception of levodopa formulations, tapered off within 14 days after randomization 
according to the prescribing information and the discretion of the Investigator.  
Section 5.2.3.2  Concomitant Therapy
Subsection General Requirements
Heading "Randomization to End of Treatment Period:"
Last bullet, second sentence previously read:
Time of inverse titration should be done following the individual medications' SmPC and 
at the Investigator's discretion, but should not exceed 14 days after randomization.  
Has been changed to read:
Time of inverse titration should be done following the prescribing information and the 
Investigator's discretion, but should not exceed 14 days after randomization.  
Section 5.6.1  Discussion of Study Design and Choice of Control Groups
Item 5 previously read:
Per the SmPC, Duodopa is initiated as monotherapy – tapering off of all other anti-PD 
medications besides levodopa at initiation would not be plausible in a blinded study
Has been changed to read:
Per the Package Leaflet, Duodopa is initiated as monotherapy – tapering off of all other 
anti-PD medications besides levodopa at initiation would not be plausible in a blinded 
study
Section 6.1.1.3  Adverse Events of Special Interest
"Neuroscience Clinical Safety Management Team" 
"Bldg." previously read:


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Has been changed to read:
Section 6.1.3  Relationship to Study Drug
Delete:  second paragraph
For a randomized study with an OMT arm:  
Section 6.1.5  Adverse Event Reporting
"Neuroscience Clinical Safety Management Team" 
"Bldg." previously read:
Has been changed to read:
Section 6.1.5  Adverse Event Reporting
"Primary Therapeutic Area Medical Director" 
"Bldg." previously read:
Has been changed to read:
Section 6.1.5  Adverse Event Reporting
Last paragraph
Delete:  second sentence
The reference document used for SUSAR reporting in the EU countries will be the most 
current version of the Investigator's Brochure.  


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Section 6.1.5  Adverse Event Reporting
Last paragraph, last sentence previously read:
The reference document used for SUSAR reporting in the EU countries will be the most 
current version of the Summary of Product Characteristics (SmPC).
Has been changed to read:
The reference document used for SUSAR reporting in the EU countries will be the most 
current version of the Investigator's Brochure.
Section 14.0  Investigator's Agreement
Item 1 previously read:
I have received and reviewed the country specific approved product label for 
Levodopa-Carbidopa Intestinal Gel and for subjects randomized to OMT will review the 
product label for the subjects' respective OMT.
Has been changed to read:
I have received and reviewed the Investigator's Brochure for Levodopa-Carbidopa 
Intestinal Gel and for subjects randomized to OMT will review the product label for the 
subjects' respective OMT.
Section 15.0  Reference List
Reference 42 previously read:
AbbVie.  Levodopa-Carbidopa Investigator's Brochure Edition 7.  14 July 2011.
Has been changed to read:
AbbVie.  Levodopa-Carbidopa Investigator's Brochure Edition 12.  07 April 2017.


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
GDSM
Statistics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Clinical
Clinical
CDSM
Statistics

SAP_001.pdf: 
Levodopa-Carbidopa Intestinal Gel (LCIG)
M12-927 – Statistical Analysis Plan
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1.0
Title Page
Statistical Analysis Plan
Study M12-927
An Open-Label, Randomized 26-Week Study 
Comparing Levodopa-Carbidopa INteStInal Gel 
(LCIG) THerapy to Optimized Medical Treatment 
(OMT) on Non-Motor Symptoms (NMS) in Subjects 
with Advanced Parkinson's Disease
INSIGHTS Study
Date:  11 Apr 2018
Version 2.0
NCT02549092


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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................6
4.0
Study Objectives, Design and Procedures............................6
4.1
Objectives .............................................................................................. 6
4.2
Design Diagram ..................................................................................... 6
4.3
Sample Size.......................................................................................... 13
4.4
Interim Analysis................................................................................... 14
4.5
Efficacy and Health-Related Outcome Measures .................................. 14
4.5.1
Non-Motor Symptoms.......................................................................... 14
4.5.2
Motor Symptoms.................................................................................. 14
4.5.3
Health-Related Outcomes..................................................................... 14
4.6
Safety Measures ................................................................................... 15
5.0
Analysis Populations ........................................................... 15
6.0
Analysis Conventions .......................................................... 16
6.1
Statistical Significance ......................................................................... 16
6.2
Definition of Study Epochs and LCIG Treatment Period 
Reference Variables ............................................................................. 17
6.3
Definition of Baseline and Final Observation ....................................... 19
6.4
Analysis by Planned Visit..................................................................... 20
6.5
Analysis of Vital Signs by Planned Time.............................................. 23
6.6
Adverse Event Analysis by Study Week............................................... 24
6.7
Derived Datasets .................................................................................. 24
7.0
Subject Disposition, Baseline Characteristics and 
Concomitant Medications ................................................... 25
7.1
Subject Disposition............................................................................... 25
7.2
Demographic and Baseline Characteristics ........................................... 26
7.3
Medical History.................................................................................... 27
7.4
Prior and Concomitant Medications...................................................... 28
8.0
Treatment Exposure and Compliance ............................... 29
8.1
Duration of Treatment and PEG-J Exposure......................................... 29


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8.2
OMT Daily Prescribed Dose................................................................. 31
8.3
Duration of NJ Period........................................................................... 31
8.4
Duration of Initial LCIG Titration Following PEG-J Placement............ 32
8.5
LCIG Daily Prescribed Dose ................................................................ 32
8.6
Total Daily Levodopa Dose.................................................................. 33
8.7
Daily Treatment Duration..................................................................... 34
8.8
Tube Replacements .............................................................................. 34
9.0
Efficacy and Health Outcome Analysis.............................. 34
9.1
General Considerations......................................................................... 34
9.2
Primary Efficacy Analysis.................................................................... 35
9.3
Additional Efficacy Analyses ............................................................... 37
9.4
Calculation of Efficacy and Health Outcome Variable.......................... 39
9.5
Handling of Multiplicity....................................................................... 45
9.6
Efficacy Subgroup Analysis ................................................................. 46
10.0
Safety Analysis.....................................................................46
10.1
General Considerations......................................................................... 46
10.2
Analysis of Adverse Events.................................................................. 47
10.2.1
Adverse Event Overview...................................................................... 48
10.2.2
Adverse Event Incidence ...................................................................... 49
10.2.3
Adverse Events of Special Interest........................................................ 50
10.2.4
Adverse Events by Subgroup................................................................ 51
10.2.5
Listings of Adverse Events................................................................... 51
10.3
Analysis of Laboratory Tests................................................................ 52
10.3.1
Analysis of Mean Changes for Laboratory Tests................................... 52
10.3.2
Shifts Between Normal and Abnormal for Laboratory Tests................. 53
10.3.3
Potentially Clinically Significant (PCS) Laboratory Values .................. 54
10.4
Analysis of Vital Signs and Weight ...................................................... 54
10.4.1
Vital Sign and Weight Mean Changes .................................................. 54
10.4.2
Shifts in BMI Category......................................................................... 55
10.4.3
Potentially Clinically Significant (PCS) Vital Sign and Weight 
Values .................................................................................................. 55
10.5
Analysis of Electrocardiogram (ECG) Variables................................... 56
10.5.1
ECG Mean Changes ............................................................................. 56


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10.5.2
Potentially Clinically Significant (PCS) ECG Values ........................... 57
10.6
Analysis of Sleep Attack Questions ...................................................... 57
10.7
Analysis of Minnesota Impulsive Disorders Interview (MIDI).............. 58
10.8
Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS)............ 59
11.0
Special Statistical Topics..................................................... 60
12.0
Summary of Changes .......................................................... 60
13.0
Appendices........................................................................... 60
List of Tables
Table 1.
Analysis Windows for Efficacy Variables ............................................ 20
Table 2.
Analysis Windows for Safety Variables During the 26-Week 
Treatment Period.................................................................................. 21
Table 3.
Analysis Windows for Safety Variables During the 
Extension/Transition Period for the LCIG Group.................................. 22
Table 4.
Analysis Windows for Safety Variables During the 
Extension/Transition Period for the OMT Group.................................. 23
Table 5.
Analysis Windows for Vital Signs on the Day of LCIG Infusion 
for the LCIG Group.............................................................................. 24
Table 6.
Analysis Windows for Treatment Emergent Adverse Events 
During the 26-Week Treatment Period ................................................. 24
Table 7.
Primary and Secondary Efficacy Variables, and Derivations................. 40
List of Figures
Figure 1.
Study Design Schematic (All Countries Except for United States 
and South Korea).................................................................................... 9
Figure 2.
Study Design Schematic (United States)................................................. 9
Figure 3.
Study Design Schematic (South Korea) ................................................ 11
List of Appendices
Appendix A.
Study Activities.................................................................................... 61


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Appendix B.
Study Activities For South Korea Subjects Entering the Extension 
Period from the OMT Arm ................................................................... 66
Appendix C.
Study Activities For South Korea Subjects Entering the Extension 
Period from the LCIG Arm................................................................... 69
Appendix D.
Study Activities For United States Subjects Entering Part 2 from 
the OMT Arm....................................................................................... 71
Appendix E.
Study Activities For United States Subjects Entering the 
Extension Period from the LCIG Arm .................................................. 74
Appendix F.
Potentially Clinically Significant Laboratory Values ............................ 76
Appendix G.
Criteria for Potentially Clinically Significant Vital Sign and 
Weight Values...................................................................................... 77
Appendix H.
Criteria for Potentially Clinically Significant ECG Values.................... 78


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
AbbVie clinical statisticians for Levodopa-Carbidopa Intestinal Gel (LCIG) 
Study M12-927 with a protocol dated 25 January 2018 (original protocol:  
23 January 2015, Amendment 1:  07 May 2015, Administrative Change 1:  
27 October 2015, Amendment 2:  28 March 2016, Amendment 3:  15 November 2016, 
Administrative Change 2:  16 March 2017, Amendment 4:  31 May 2017, Administrative 
Change 3:  27 July 2017, Administrative Change 4:  02 August 2017, South Korean only 
Amendment 4.01:  13 September 2017, United States only Amendment 4.02:  
13 September 2017, United States only Administrative Change 5:  11 October 2017, 
South Korea only Administrative Change 6:  25 January 2018, United States only 
Administrative Change 7:  25 January 2018).  It provides details to further elaborate 
statistical methods as outlined in the protocol and describes analysis conventions to guide 
the statistical programming work.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or higher 
(SAS Institute Inc., Cary, NC 27513) under the Unix operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of this study is to examine the effect of LCIG relative to that of 
optimized medical treatment (OMT) on non-motor symptoms associated with advanced 
Parkinson's disease (PD) as assessed by the Non-Motor Symptoms Scale (NMSS) Total 
Score and the Modified Parkinson's Disease Sleep Scale (PDSS-2) Total Score.
4.2
Design Diagram
This is a Phase 3b, open-label, randomized multicenter 26-week study comparing LCIG to 
OMT for the treatment of non-motor symptoms in subjects with advanced Parkinson's 
disease.


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The study will consist of three sequential parts:
Part 1:  Screening period.  The screening period will consist of three visits, Visit 1 (V1), 
Visit 2 ([V2] [optional]) and the Randomization Visit (V3) in which the subject will be 
assessed to determine eligibility.  The duration of the Screening Period can be between 
30 – 67 days to accommodate the required procedures, training and collection of diaries, 
and to allow for stabilization of anti-PD medications and medications to treat NMS.  All 
anti-PD medications and medications to treat NMS are required to be stable for a 
minimum of 30 days prior to randomization.
Part 2:  Treatment period.  Those subjects randomized to OMT at the end of V3 will 
remain on their current optimized regimen.  The day after randomization will be 
considered Day 1 of their treatment period and subjects will have study visits at the end of 
Weeks 2, 6, 12, and 26.  All subjects randomized to the LCIG group should have all 
anti-PD medications, with the exception of levodopa formulations, tapered off within 
14 days after randomization.  Optional nasojujunal and/or percutaneous endoscopic 
gastrostomy with a jejunal tube (PEG-J) placement will then be placed.  After that, the 
subject may begin initiation and titration of LCIG infusion to be adjusted to obtain the 
optimal clinical response in 14 days.  The day of initial NJ or PEG-J placement will be 
considered Day 1 for subjects in the LCIG group.  Study visits happen at the end of 
Weeks 2, 6, 12, and 26.
Part 3:  Extension Period.  Subjects in the United States or South Korea from both 
treatment arms who complete the 26 week study may continue into the Extension Period 
of the study.  South Korea subjects in the LCIG arm will have study drug dispensation 
every 4 weeks and will have study visits every 6 months.  South Korea subjects from the 
OMT arm will undergo the NJ (optional) and PEG-J procedures, titration, plus have visits 
at 2 weeks, 6 weeks, 3 months and 6 months post NJ or PEG-J.  Subjects will then 
continue to receive study drug every 4 weeks and will have study visits every 6 months 
until Duodopa is commercially available.


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United States subjects in LCIG arm will continue to have study drug dispensation every 
4 weeks and will have study visits at 3 and 6 months, or the day prior to transition to 
commercial if that happens before the scheduled study visits.  United States subjects from 
the OMT arm will undergo the NJ (optional) and PEG-J procedures, titration, plus have 
visits at 2 weeks, 6 weeks, 3 months and 6 months post NJ or PEG-J, or the day prior to 
transition to commercial if that happens before the scheduled study visits.  Subjects will 
receive study drug every 4 weeks.  The Extension Period will last for a maximum of 
6 months to allow for continuity of care while the transition to commercially available 
drug occurs.
Part 4:  Follow-up period.  For subjects who elect to discontinue LCIG treatment at any 
time during the study, the PEG-J tube will be removed following the End of Study 
activities.  A follow-up clinic visit will occur approximately 1 week later.  For study 
subjects who complete participation in the study and will continue to receive LCIG, 
subjects will return every 6 weeks to return used LCIG cassettes and be dispensed 
cassettes.  Additional visits every 12 weeks from Week 26 will be scheduled to monitor 
subject safety and allow for drug resupply until the subject transfers to commercial LCIG.


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Figure 1.
Study Design Schematic (All Countries Except for United States 
and South Korea)
Figure 2.
Study Design Schematic (United States)


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Extension Period:
OMT Subjects


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LCIG Subjects
Figure 3.
Study Design Schematic (South Korea)


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Extension Period:
OMT Subjects


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LCIG Subjects
4.3
Sample Size
Approximately 88 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either optimized medical treatment or LCIG.  There are no data on NMSS or PDSS-2 
available from randomized trials comparing LCIG and OMT.  Interim data from ongoing 
Phase 3b Study M12-920 showed that the improvement in NMSS total score from 
baseline to Week 12 is 24.8 in the LCIG group with standard deviation of 24.  Results 
from Zibetti et al (2013) showed that the improvement in PDSS 2 total score after an 
average of 3.5 months of LCIG treatment was 13.1.  The standard deviation was not 
provided and is estimated to be 12.2 assuming the correlation between baseline and 
follow-up visits is 0.5.
The significance level for this study is 0.05.  For sample size determination, it is assumed 
that the improvement in the OMT group is 33% of the LCIG group, i.e., the improvement 
is 8.2 on NMSS total score and 4.3 on PDSS-2 total score, and that the correlation 
between these 2 measures is 0.5.  Simulation showed that a study with 37 subjects per 


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group will have 90% power to declare statistical significance on at least one of these 
2 alternative primary endpoints after multiplicity adjustment using Hochberg procedure.  
It is further assumed that 10% of randomized subjects in either treatment group will not 
provide post-randomization efficacy assessment.  Additional simulations showed that 
44 subjects per group will provide 90% power in the sensitivity analysis using baseline 
observation carried forward for subjects without post-randomization assessment.  
Therefore the total planned enrollment is decided to be 88 subjects.
4.4
Interim Analysis
After all randomized subjects have completed the 26-week Treatment Period, or have 
discontinued during the Treatment Period and those randomized to LCIG have completed 
Follow-up Period, the primary objective of the study will have been fulfilled.  A database 
lock will occur.  Primary analyses of efficacy and safety data comparing LCIG and OMT 
arms will be conducted at that time.
4.5
Efficacy and Health-Related Outcome Measures
4.5.1
Non-Motor Symptoms
The burden of non-motor symptoms of Parkinson's disease will be evaluated using the 
Non-Motor Symptom Scale (NMSS) and Modified Parkinson's Disease Sleep Scale 
(PDSS-2).
4.5.2
Motor Symptoms
Motor symptoms will be assessed by Unified Parkinson's Disease Rating Scale (UPDRS) 
Parts III and IV.
4.5.3
Health-Related Outcomes
Health-related outcomes will be assessed by the following measures.
●
Parkinson's Disease Questionnaire-8 (PDQ-8)
●
Clinical Global Impression – Change (CGI-C)


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●
Unified Parkinson's Disease Rating Scale (UPDRS Parts I and II)
●
Patient Global Impression of Change (PGIC)
●
Parkinson Anxiety Scale (PAS)
●
Geriatric Depression Scale (GDS-15)
●
King's PD Pain Scale
A description of each measure is included in Protocol Section 5.3.1.1 Study Procedures.  
Each measure will be assessed at the times indicated in the relevant study activities flow 
chart (Appendix A).
4.6
Safety Measures
Safety and tolerability over the course of the study will be assessed by the following 
measures.
●
Adverse event monitoring 
●
Neurological exams 
●
Clinical laboratory evaluations (including special labs to detect vitamin 
deficiencies)
●
Electrocardiogram 
●
Vital signs and weight 
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Minnesota Impulsive Disorders Interview (MIDI)
●
Sleep Attacks Questionnaire (SAQ)
A description of each measure is included in Protocol Section 5.3.1.1 Study Procedures.  
Each measure will be assessed at the times indicated in the study activities flow chart 
(Appendix A).
5.0
Analysis Populations
Analyses will be performed utilizing the following datasets.


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Intent-to-Treat Dataset
The intent-to-treat dataset will include all subjects who are randomized to the optimized 
medical treatment, and all subjects who are randomized to LCIG and received at least 
one dose of study drug.  The intent-to-treat dataset will be used to summarize efficacy and 
health outcome measures.
Safety Dataset
The safety dataset will include all subjects who are randomized to the optimized medical 
treatment, and all subjects who are randomized to LCIG and have study device (NJ and/or 
PEG-J) placement.  The safety dataset will be used to summarize safety data during the 
OMT and LCIG treatment period.
All Randomized Dataset
The all randomized dataset will include all subjects who are randomized to the optimized 
medical treatment, and all subjects who are randomized to LCIG treatment.  The all 
randomized dataset will be used to perform sensitivity analysis.
6.0
Analysis Conventions
6.1
Statistical Significance
This is a randomized open-label study.  Unless otherwise specified, statistical tests will be 
two-sided and the null hypothesis will be rejected at the significance level of α = 0.050.  
P values will be rounded to three decimal points before assessing statistical significance.  
Adjustments for multiple comparisons for the two primary endpoints will be made using 
the Hochberg procedure.  If the primary endpoints are statistically significant, a Hochberg 
procedure will be used to test the 3 key secondary efficacy variables.


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6.2
Definition of Study Epochs and LCIG Treatment Period 
Reference Variables
The following study epochs have been defined to track each subject's progression from 
screening through study completion or premature discontinuation.
Epoch Name
Epoch Description
Pre
OMT group:  prior to and including the day of randomization.
LCIG group:  prior to the day of initial device (NJ or PEG-J) placement. 
Device Before in 
Randomized 
Treatment Period 
(LCIG group only)
From the date of the first device (NJ or PEG-J) placement procedure up to, but 
not including, the date of the first LCIG infusion for subjects in the LCIG group 
during the 26-week randomized treatment period.  This Epoch is missing for 
subjects whose infusion started the same day as initial device placement.
Open in 
Randomized 
Treatment Period
OMT group:  from the day after randomization through the end of study (date of 
last visit) during the 26-week randomized treatment period.  LCIG group:  from 
the date of the first LCIG infusion through the date of the last LCIG infusion 
during the 26-week randomized treatment period.
Pre in Extension 
Period (OMT group 
entering Extension 
Period only)
From the day after the last visit during 26-week randomized treatment period up 
to, but not including date of the first device (NJ or PEG-J) placement.
Device Before in 
Extension Period 
(OMT group 
entering Extension 
Period only)
From the date of the first device (NJ or PEG-J) placement procedure up to, but 
not including, the date of the first LCIG infusion. 
Open in Extension 
Period
For subjects in OMT group entering extension period:  from the date of the 
first LCIG infusion through the date of the last LCIG infusion. 
For subjects in LCIG group entering extension period:  from the date after the last 
LCIG infusion during the 26-week randomized treatment period through the date 
of the last LCIG infusion during the extension period.
Device After 
From the first day after the last LCIG infusion through the date of the final device 
removal (Note:  Subjects who have their last infusion on the same date as their 
final device removal will progress directly from the Open in Randomized 
Treatment Period/Open in Extension Period to the Off epoch).
Off
Time period after final device removal for subjects who are discontinuing LCIG 
treatment.  Time period after end of study (date of last visit) for all other subjects.
For subjects randomized to the LCIG group, the date and time of the earliest LCIG tube 
placement (NJ or PEG-J) recorded on the Device Information eCRF will be considered 


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the treatment start reference date (REFDT1) and time (DMREFTM).  The date of the last 
LCIG tube removal, or the date of the last LCIG infusion if there is no device removal in 
the 26-week randomized period will be considered as end of the LCIG 26-week 
randomized treatment period and the following day will be the post-treatment start 
reference date (REFEDT1).  For LCIG subjects who enter the Extension Period, treatment 
start reference date in extension period (REFDT2) equals REFEDT1.  The date of the last 
LCIG tube removal or the date the last LCIG infusion if there is no device removal, will 
be the post-treatment reference date (REFEDT2) of Extension Period. 
For subjects in the OMT group, the date after randomization will be considered the 
treatment start reference date (REFDT1).  The date of the final visit during 26-week 
randomized period will be considered the end of the OMT treatment period and the 
following day will be the post-treatment start reference date (REFEDT1).  For OMT 
subjects who enter the Extension Period, the date of earliest LCIG tube placement (NJ or 
PEG-J) recorded on the Device Information eCRF will be considered the treatment start 
reference date (REFDT2) in Extension period.  The date of the last LCIG tube removal, or 
the date the last LCIG infusion if there is no device removal, will be considered the end of 
the Extension Period and the following day will be the post-treatment start reference date 
(REFEDT2).  
Study Days during 26-week randomized treatment period will be calculated based on the 
treatment start reference date (REFDT1).  For time points before REFDT1, the Study 
Day = time point – REFDT1.  For time points on or after REFDT1, the Study Day = time 
point – REFDT1 + 1.  Thus, the Study Day is a negative value when the time point of 
interest is prior to REFDT1 and the Study Day is a positive value when the time point of 
interest is on or after REFDT1.  There is no Study Day 0.  The Study Day will be labeled 
as Rx Day on the data listings.  Study Days during Extension Period will be calculated 
based on the Extension Period start reference date (REFDT2) with the same rule as in 
26-week randomized treatment period.  For OMT subjects who enter the Extension 
Period, the study day of Pre in Extension Period will be calculated based on REFDT2. 


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6.3
Definition of Baseline and Final Observation
Baseline for efficacy, health outcome and safety measures during the 26-week 
randomized treatment period will be defined as the last non-missing observation that is on 
or before the day of randomization. 
Baseline for safety assessment during the Extension Period is defined as the last 
non-missing observation that is on or before the day of NJ/PEG-J placement for OMT 
subjects who enter the Extension Period.  For LCIG subjects who enter the Extension 
Period, baseline of 26-week randomized treatment period will be used as the baseline of 
Extension Period. 
The final visit for efficacy and health outcome measure will be defined as the last non-
missing observation that is after the day of randomization for the OMT group during the 
26-week randomized treatment period.  The final visit for efficacy and health outcome 
measures for the LCIG group will be defined as the last non-missing observation that is 
after the date of the first LCIG infusion following PEG-J placement and no more than 
1 day after the last LCIG infusion during the 26-week randomized treatment period. 
The final observation for safety assessment during the 26-week randomized Treatment 
Period is defined as:
●
For subjects in the OMT group and LCIG subjects who enter the 
Extension/Transition Period:  the last non-missing observation that is after the 
day of randomization (for the OMT group) or after the initial device placement 
(for the LCIG group) and during the 26-week randomized treatment period. 
●
For LCIG subjects who do not enter the Extension/Transition Period:  the last 
non-missing observation that is after the date and time of the first LCIG tube 
(NJ or PEG-J) placement procedure and no more than 1 day after the final 
removal of all LCIG tubes during the 26-week randomized treatment period.  


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The final observation for safety assessment during the Extension/Transition Period is 
defined as last non-missing observation for OMT/LCIG subjects who enter the 
Extension/Transition period. 
Safety assessments on the date of the initial device placement procedure that do not have a 
time of assessment or sample collection recorded will be assumed to be post-procedure.  
6.4
Analysis by Planned Visit 
A midpoint convention will be used to assign all observations to a planned visit based on 
the Study Day of the observation.  If there are multiple observations on the same day, the 
average will be taken and considered the observation for the day.  If more than 
one observation is assigned to a planned visit, the last observation will be selected and 
considered the observation for the planned visit.
The following Study Day windows will be used to assign efficacy and health outcome 
assessments to planned study visits during 26-week randomized treatment period.  
Table 1.
Analysis Windows for Efficacy Variables
Assessment
Planned Visit
Nominal Study Day
Study Day Rangea
NMSS, PDSS-2, PDQ-8, 
PAS, GDS-15, UPDRS 
and King's PD Pain Scale
Baseline
≤ date of randomization
Week 6
42
2 – 63
Week 12
84
64 – 133
Week 26
182
134 – 222
CGI-C and PGIC
Week 26
182
≥ 2
a.
For subjects in LCIG group, all post-baseline assessments must also be after start of LCIG infusion through PEG-J 
and no more than 1 day after the date of the last LCIG infusion in the 26-week Treatment Period.
The following Study Day windows will be used to assign safety assessments to planned 
study visits.


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Table 2.
Analysis Windows for Safety Variables During the 26-Week 
Treatment Period
Assessment
Planned Visit
Nominal Study 
Day
Study Day Rangea
Vital signs and 
weight
Baseline
≤ date of randomization
Week 2
14
2 – 28
Week 6
42
29 – 63
Week 12
84
64 – 133
Week 26
182
134 – 186
Week 27 FUb
189
187 – 301
Clinical labs and 
Electrocardiograms
Baseline
≤ date of randomization
Week 12
84
2 – 133
Week 26
182
> 133
Special labs
Baseline
≤ date of randomization
Week 12
84
2 – 133
Week 26
182
134 – 231
a.
For subjects in LCIG group, all post-baseline assessments must also be no more than 1 day after the final PEG-J 
removal for subjects who have their study device removed after their last infusion of Study M12-927 LCIG.
b.
Applicable only to LCIG subjects who will not transition to commercial LCIG and have study device removed.
The following Study Day windows for Extension Period will be used to assign safety 
assessments to planned study visits for LCIG subject entering Extension Period.


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Table 3.
Analysis Windows for Safety Variables During the 
Extension/Transition Period for the LCIG Group
Assessment
Planned Visit
Nominal Study 
Day
Study Day Rangea
Vital signs and weight, 
Clinical labsa, 
Electrocardiogramsa, 
and special labs
Baselineb
≤ date of last visit in 26-week 
randomized treatment period for 
subjects randomized to LCIG 
group. 
Month 3c
84
1 – 126
Month 6
168
127 – 200
Every 3 months 
following until 
subjects' 
transition to 
commercial 
LCIG
Previous + 84
Previous lower bound + 84 through 
previous upper bound + 84
a.
Clinical labs and Electrocardiograms will not be collected during the Transition Period. 
b.
Baseline refers the baseline of Extension Period.  All days refer to study day in Extension Period.  All post-baseline 
assessments must also be no more than 1 day after the final PEG-J removal for subjects who have their study 
device removed after their last infusion of Study M12-927 LCIG.
c.
Applicable only to US subjects.
The following Study Day windows for Extension Period will be used to assign safety 
assessments to planned study visits for OMT subject entering Extension Period.


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Table 4.
Analysis Windows for Safety Variables During the 
Extension/Transition Period for the OMT Group
Assessment
Planned Visit
Nominal Study 
Day
Study Day Rangea
Vital signs and weight, 
Baselinea
< date of NJ/PEG-J placement for 
subjects randomized to OMT group 
and entering Extension Period
Week 2
14
2 – 28
Week 6
42
29 – 63
Month 3
84
64 – 126
Month 6
168
127 – 200
Every 3 months 
following until 
subjects' 
transition to 
commercial 
LCIGc
Previous + 64
Previous lower bound + 84 through 
previous upper bound + 84
Clinical labsb, 
Electrocardiogramsb, 
and special labs
Baselinea
< date of NJ/PEG-J placement for 
subjects randomized to OMT group 
and entering Extension Period
Month 3
84
2 – 126
Month 6
168
127– 252
Every 3 months 
following until 
subjects' 
transition to 
commercial
Previous + 168
Previous lower bound + 168 
through previous upper 
bound + 168
a.
Baseline refers the baseline of Extension Period.  All days refer to study day in Extension Period.  All post-baseline 
assessments must also be no more than 1 day after the final PEG-J removal for subjects who have their study 
device removed after their last infusion of Study M12-927 LCIG.
b.
Clinical labs and Electrocardiograms will not be collected during the Transition Period.  
6.5
Analysis of Vital Signs by Planned Time
Vital sign measurements were to be performed at hourly intervals on the first day of LCIG 
infusion via NJ and via PEG-J.  Observations on the first day of LCIG infusion will be 
assigned to a planned time based on the time of assessment relative to the reported start 
time of the first LCIG infusion as follows.


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Table 5.
Analysis Windows for Vital Signs on the Day of LCIG Infusion for 
the LCIG Group
Planned Time
Nominal Relative Time (Minutes)
Relative Time Range (Minutes)
Hour 0
0
≤ 0
Hour 1
60
> 0 – 90
Hour 2
120
91 – 150
Hour 3
180
> 150
6.6
Adverse Event Analysis by Study Week
Treatment-emergent adverse events will be assigned to study week intervals based on the 
Study Day of onset as follows.
Table 6.
Analysis Windows for Treatment Emergent Adverse Events During 
the 26-Week Treatment Period 
Study Week(s)
Study Day Range
Week 1
1 – 7
Week 2
8 – 14
Week 3
15 – 21
Week 4
22 – 28
Week 5
29 – 35
Weeks 6 – 26
36 – 182
6.7
Derived Datasets
The study database will include the following derived datasets which will be used for the 
analyses described in this SAP. 
●
Subject Characteristics for all subjects who participated in the study:  
one record per subject with demographic, baseline characteristic, analysis 
population and subgroup variables.
●
Study Drug Exposure during the 26-week randomized Treatment Period for 
the Safety Dataset:  For LCIG subjects, one record per subject for each 


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exposure variable (morning dose, extra dose, etc.) and each planned 
assessment time with the prescribed dose and actual dose.  For OMT subjects, 
one record per subject per medication. 
●
Efficacy Endpoints for the All Randomized Dataset:  one record per subject for 
each variable and each planned assessment time with the baseline value, time 
point value, and change from baseline value for the NMSS, PDSS-2, UPDRS, 
PDQ-8, CGI-C, PGIC, PAS, GDS-15 and King's PD Pain Scale total and 
domain scores.
A Derived Dataset Specification that includes a detailed description of the dataset's 
structure and variables will be developed for each derived dataset.
7.0
Subject Disposition, Baseline Characteristics and 
Concomitant Medications
7.1
Subject Disposition
An overall summary of the disposition of all screened subjects will be prepared.  The total 
number of subjects in each of the following categories as well as the number at each site 
will be presented:  
●
Screened, screen failed; 
●
Randomized to OMT group, prematurely discontinued treatment from OMT 
group, completed the planned 26 weeks of treatment in OMT group, continued 
to Extension Period, prematurely discontinued during the Extension Period, 
completed the Extension Period; Randomized to LCIG group, no NJ/PEG-J 
placed, NJ placed, prematurely discontinued during NJ, PEG-J placed, 
prematurely discontinued treatment during PEG-J, completed the planned 
26 weeks of treatment in LCIG group, continued to Extension Period, 
prematurely discontinued during the Extension Period, completed the 
Extension Period. 


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An additional summary of screen failures will be prepared with the number and 
percentage of screened subjects who screen failed overall and for each specific screen 
failure reason. 
Additional summaries of premature study drug discontinuations during the 26-week 
Treatment Period for both treatment groups, and during the Extension/Transition Period, 
will be prepared for the Safety Dataset with the number and percentage of subjects who 
prematurely discontinued for any reason, for each specific primary reason, and for each 
specific reason.
A listing will be prepared of all randomized subjects who are not included in the primary 
efficacy analysis.  The listing will include each subject number and reason for exclusion.
7.2
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment 
group and for overall subjects in the safety dataset unless otherwise specified.
●
Gender (male/female)
●
Race (white, black, American Indian/Alaska native, native Hawaiian or other 
Pacific Islander, Asian, Other, Multi-Race)
●
Ethnicity (Hispanic or Latino, ne)
●
Age (years)
●
Age category (< 65, ≥ 65)
●
Age category (< 75, ≥ 75)
●
Weight for all subjects (kg)
●
Weight for all male subjects (kg)
●
Weight for all female subjects (kg)
●
Height (cm)
●
Body mass index (BMI, kg/m2)
●
Body mass index category (< 25 kg/m2, ≥ 25 kg/m2)
●
Mini-Mental State Examination (MMSE) total score


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●
Parkinson's disease duration (years)
●
Motor fluctuation duration (years)
●
Parkinson's disease duration category (< 10 years, ≥10 years)
●
Time from Parkinson's disease diagnosis to start of first levodopa medication 
(years)
●
Proportion of subjects meeting each of the following United Kingdom 
Parkinson's Disease society (UKPDS) Brain Bank diagnostic criteria for PD
○
Diagnosis of bradykinesia
○
Diagnosis of muscular rigidity
○
Diagnosis of 4 – 6 Hz resting tremor
○
Diagnosis of postural instability
Alcohol and nicotine use will also be summarized.  For alcohol use the number and 
percentage of subjects who are drinkers, ex-drinkers and non-drinkers (defined as those 
who have never been a drinker) will be presented.  For nicotine use the number and 
percentage of users, ex-users and non-users (defined as those who have never been a user) 
will be presented.  A subject reporting multiple use categories for the different types of 
nicotine (cigarettes, pipes, cigars and chewing tobacco) will be counted in the nicotine use 
category closest to user.
Categorical variables will be summarized with the number and percentage of subjects in 
each category.  Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum and 
maximum).
7.3
Medical History
The conditions/diagnoses recorded in medical/surgery history eCRF will be coded using 
the most current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Medical/surgical history data will be summarized by primary MedDRA system organ 
class (SOC) and preferred term (PT) for each treatment group and overall subjects in the 
Safety Dataset.  Subjects reporting more than one condition/diagnosis for a given PT will 


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be counted only once for that term.  Subjects reporting more than one condition/diagnosis 
within an SOC will be counted only once for the SOC total.  Subjects reporting more than 
one condition/diagnosis will be counted only once in the overall medical history total.  
The SOCs will be presented in alphabetical order and the PTs will be presented in 
alphabetical order within each SOC.
7.4
Prior and Concomitant Medications
Medications prescribed for the treatment of Parkinson's disease (anti-PD medications) will 
be identified by the investigator and will be entered into the database and summarized 
separately from other medications.  All medications will be coded using the World Health 
Organization (WHO) dictionary and will be summarized by generic name.
Summaries of 3 categories of anti-PD medications (anti-PD motor symptom medications, 
anti-PD non-motor symptom medications, and anti-PD sleep medications) will be 
prepared for the Safety Dataset for the following periods:
●
from V1 prior to Day 1 
●
during the 26-week randomized treatment period (start date before or on the 
last date of the 26-week treatment Period and end date on or after Day 1)
Each summary will include the number and percentage of subjects who took each specific 
medication, each incremental number of medications (1, 2, 3, 4, 5, and 6 or more) and 
each cumulative number of medications (1 or more, 2 or more, 3 or more, 4 or more, and 
5 or more).  For the summary of anti-PD motor symptom medications, the count will be 
for medications other than levodopa-carbidopa.
The following summaries of other medications will be prepared for the Safety Dataset.
●
Other medications prior to treatment (start date before Day 1)
●
Other medications during the 26-week randomized treatment period (start date 
before or on the last date of the 26-week randomized treatment period and end 
date on or after Day 1)


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Each summary will include the number and percentage of subjects who took each specific 
medication and the number who took 1 or more medications.
8.0
Treatment Exposure and Compliance
Summaries of treatment exposure and compliance will be prepared for the Safety Dataset.
8.1
Duration of Treatment and PEG-J Exposure
During the 26-Week Randomized Treatment Period
The duration of study drug exposure for LCIG subjects and the duration of study 
participation for OMT subjects during the 26-week randomized Treatment Period will be 
summarized with descriptive statistics (number of subjects with non-missing data, mean, 
standard deviation, median, minimum and maximum).  In the 26-week randomized 
treatment period, the duration of LCIG study drug exposure will be calculated for each 
subject as the date of the last dose of LCIG study drug during the randomized treatment 
period minus the date of the first dose of LCIG study drug plus 1.  The duration of study 
participation for OMT subjects will be calculated for each subject as the date of the last 
visit during the 26-week randomized treatment period minus the date of randomization.
For subjects with a PEG-J tube removal after their last infusion of Study M12-927 study 
drug during the 26-Week Randomized Treatment Period, the duration of PEG-J exposure 
for each subject will be calculated as the date of their final PEG-J removal minus the date 
of their initial PEG-J placement + 1.  For subjects without a PEG-J tube removal after 
their last infusion of study drug during the 26-Week Randomized Treatment Period, the 
duration of PEG-J exposure during the 26-Week Randomized Treatment Period for each 
subject will be calculated as the date of their final participation in Study M12-927 (last 
contact or visit date) during the 26-Week Randomized Treatment Period minus the date of 
their initial PEG-J placement + 1.


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The number and percentage of subjects in each of the following exclusive duration 
categories will be summarized for LCIG infusion exposure in the LCIG group and study 
participation for the OMT group.
●
1 to 28 days (1 – 4 weeks)
●
29 to 56 days (5 – 8 weeks)
●
57 to 84 days (9 – 12 weeks)
●
≥ 85 days (≥ 13 weeks)
In addition, duration of exposure will be summarized with descriptive statistics (number 
of non-missing observations, mean, standard deviation, median, minimum and maximum 
duration and total subject-years) and by total subject-years.  Total subject-years of OMT, 
LCIG exposure and PEG-J exposure will be calculated by summing the duration of 
exposure across the respective set of subjects and dividing this sum by 365.25 (1 year will
be considered to be 365.25 days).
During the Extension Period
For LCIG subjects who continue LCIG exposure after the 26-week randomized treatment 
period, the continuing LCIG exposure will be calculated as the last day of LCIG study 
drug in Extension Period minus the date of the last dose of LCIG study drug during the 
26-week randomized treatment period.  The first and last treatment dates will be recorded 
on the Study Drug Administration eCRF.
For OMT subjects who continue into Extension Period, the duration of LCIG study drug 
exposure during Extension Period will be calculated for each subject as the date of the last 
dose of LCIG study drug minus the date of the first LCIG infusion plus 1.  
For LCIG subjects who continue with a PEG-J tube after the 26-week randomized 
treatment period, and with a PEG-J tube removal after their last infusion of 
Study M12-927 study drug, the duration of PEG-J exposure for each subject will be 
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participation in Study M12-927 (last contact or visit date) during the 26-Week 
Randomized Treatment Period + 1.  For subjects without a PEG-J tube removal after their 
last infusion of study drug, the duration of PEG-J exposure for each subject will be 
calculated as the date of their final participation in Study M12-927 (last contact or visit 
date) minus the date of their final participation in Study M12-927 (last contact or visit 
date) during the 26-Week Randomized Treatment Period + 1.
For OMT subjects who continue into Extension Period and with a PEG-J tube removal 
after their last infusion of Study M12-927 study drug, the duration of PEG-J exposure for 
each subject will be calculated as the date of their final PEG-J removal minus the date of 
their initial PEG-J placement + 1.  For OMT subjects who continue into Extension Period
and without a PEG-J tube removal after their last infusion of study drug, the duration of 
PEG-J exposure for each subject will be calculated as the date of their final participation 
in Study M12-927 (last contact or visit date) minus the date of their initial PEG-J 
placement + 1.
8.2
OMT Daily Prescribed Dose
Those subjects randomized to OMT, will continue on their current anti-PD medication 
regimen for the duration of the 26-week randomized treatment period.  All anti-PD 
medications should remain stable for the duration of the study unless adjustments are 
needed if medically justified.  The PI will provide the prescription for continued OMT.  
Use of medications to treat sleep disorders on an, as needed basis, are prohibited.
8.3
Duration of NJ Period
Duration of NJ Period for each subject who undergoes the optional NJ period will be 
calculated as the date of NJ removal minus the first NJ infusion date + 1.  The first NJ 
infusion date will be recorded on the Study Drug Administration eCRF.  The number and 
percentage of subjects with each specific number of days will be summarized.  In 
addition, the duration of NJ Period in days will be summarized with descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum and 
maximum duration).


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8.4
Duration of Initial LCIG Titration Following PEG-J Placement 
Duration of initial LCIG titration for each subject will be calculated as the date of the 
first optimized prescription following PEG-J placement minus the first LCIG infusion 
date via PEG-J + 1.  The first LCIG infusion date will be recorded on the Study Drug 
Administration eCRF.  The current LCIG pump settings at the conclusion of each clinic 
visit will be recorded on the Study Drug Prescription eCRF.  The first set of pump settings 
that remains unchanged for at least 7 days will be considered the first optimized 
prescription.  The number and percentage of subjects with each specific number of 
titration days will be summarized.  In addition, the duration of initial titration in days will 
be summarized with descriptive statistics (number of non-missing observations, mean, 
standard deviation, median, minimum and maximum duration).
8.5
LCIG Daily Prescribed Dose
Each subject's LCIG dose will be individually titrated by adjustment of the LCIG pump 
settings for the morning dose (mL), continuous flow rate (mL/hr) and extra dose amount 
(mL).  The initial LCIG pump settings and the LCIG pump settings at the conclusion of 
each clinic visit will be recorded on the Study Drug Prescription eCRF.  Subjects are to 
administer LCIG over a full 16-hour period each day beginning with a morning dose.  
Extra doses are to be administered only if needed.  The daily prescribed dose will be 
calculated as the morning dose plus 16 times the continuous flow rate.  The daily 
prescribed dose will be summarized in milligrams (mg) of levodopa using the conversion 
factor of 1 mL LCIG = 20 mg levodopa.
The daily prescribed dose will be summarized with descriptive statistics (number of 
subjects with non-missing observations, mean, standard deviation, median, minimum and 
maximum values) for the following.
●
Initial LCIG prescription
●
First optimized prescription following PEG-J placement
●
Final prescription


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Descriptive statistics will also be presented for the change in the daily prescribed dose 
from initial LCIG prescription to first optimized prescription following PEG-J placement 
and to final prescription and from first optimized prescription to final prescription.
8.6
Total Daily Levodopa Dose
For all randomized subjects, the total daily levodopa dose on the day prior to Visit 1 and 
on the day of randomization will be considered the subject's screening and baseline 
levodopa dose, respectively.  Following Screening Visit 3, subjects randomized to the 
LCIG group will have NJ/PEG-J placement and discontinue all anti-PD medications other 
than levodopa-carbidopa that will be continued during LCIG treatment as post-infusion 
nighttime therapy.  Subjects in the LCIG group are to record all LCIG infusions during 
the 3 days before each scheduled study visit on a Subject Dosing Diary.  Subjects in the 
OMT group are to record all anti-parkinsonian medications taken during the 26-treatment 
period on the Subject Dosing Diary.
For each Subject Dosing Diary, the overall total daily dose of levodopa will be determined 
for each subject in the Safety Dataset, as well as the total for each dosing source for each 
subject in the LCIG group:  LCIG morning dose, LCIG continuous infusion, LCIG extra 
dose, and LCIG overall.  Each subject's average daily dose at each visit, overall and by 
dosing source, will be calculated by summing the total dose on each Subject Dosing Diary 
assigned to the visit and dividing by the number of diaries recorded.  For LCIG subjects, 
only diaries reporting at least 12.8 hours of pump operation and only diaries after the 
initial LCIG titration will be included in this calculation.
For each scheduled visit the mean daily levodopa dose will be summarized, overall and by 
dosing source, with descriptive statistics (number of subjects with observations, mean, 
standard deviation, median, minimum and maximum values).  The summaries for LCIG 
extra dose should only include the subjects who dosed in this manner at the visit.
For each scheduled visit during the Extension Period, the mean daily levodopa dose will 
be summarized, overall and by dosing source, with descriptive statistics (number of 


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subjects with observations, mean, standard deviation, median, minimum and maximum
values) will also be provided for OMT/LCIG subjects who enter the Extension Period.
8.7
Daily Treatment Duration
The LCIG pump start time and end time at each clinic visit will be recorded on the Study 
Drug Prescription eCRF.  Daily treatment duration (hours of pump operation) will be 
summarized with descriptive statistics (mean, standard deviation, median, minimum and 
maximum duration) at each visit.
8.8
Tube Replacements
The number and percentage of LCIG subjects with each specific count of PEG-J tube 
replacements will be summarized as well as the number and percentage of LCIG subjects 
with one or more replacements.  The number of PEG-J tube replacements will also be 
summarized by descriptive statistics.  The time to the first PEG-J tube replacement will 
also be estimated using Kaplan-Meier methodology.  For the Kaplan-Meier analysis, 
subjects who did not have a PEG-J tube replacement during the study will be censored at 
the end of their Study M12-927 PEG-J tube exposure.  Subjects with a PEG-J tube 
removal after their last infusion of Study M12-927 study drug will be censored at this 
final tube removal date.  Subjects without a PEG-J tube removal after their last infusion of 
Study M12-927 study drug will be censored on the date of their final participation in 
Study M12-927 (last contact or visit date).
9.0
Efficacy and Health Outcome Analysis
9.1
General Considerations
This is a randomized open-label study.  Unless otherwise specified, statistical tests will be 
two-sided and the null hypothesis will be rejected at the significance level of α = 0.050.  
P values will be rounded to 3 decimal places before assessing statistical significance.  
Unless noted otherwise, all analyses will be performed with the Intent-to-Treat Dataset.  
Missing data will not be imputed unless otherwise specified.


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9.2
Primary Efficacy Analysis
NMSS Total Score
The NMSS was developed to assess non-motor symptoms in PD.  It is obtained by 
interview and rated by health professionals.  It contains 30 questions grouped into 
9 domains as follows.
NMSS Domain
Number of Questions
Score Range
Cardiovascular including falls
2
0 – 24
Sleep/fatigue
4
0 – 48
Mood/cognition
6
0 – 72
Perceptual problems/hallucinations
3
0 – 36
Attention/memory
3
0 – 36
Gastrointestinal tract
3
0 – 36
Urinary
3
0 – 36
Sexual function
2
0 – 24
Miscellaneous
4
0 – 48
Each question is scored with respect to severity and frequency.  Severity is rated on a 
scale where 0 = none, 1 = mild, 2 = moderate and 3 = severe.  Frequency is rated on a 
scale where 1 = rarely, 2 = often, 3 = frequent, and 4 = very frequent.  Item scores are 
calculated as the product of severity and frequency.  Domain scores and a total score are 
obtained by summing the item scores.  The NMSS total score ranges from 0 to 360.  
There is no imputation of missing responses.  If one or more item scores are missing, the 
total score and respective domain score will not be calculated.
PDSS-2 Total Score
The PDSS-2 was developed from the PDSS based upon the need for a treatment-
measuring tool containing PD-specific sleep disorders.  The instrument was extended to 
address specific sleep disturbances such as restless leg syndrome (RLS), morning 
akinesia, pain, and sleep apnea.  The frequency is assessed for the 15 sleep problems 
based on a 5-point Likert-type scale (ranging from 0 [never] to 4 [very often]).  Scores are 


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calculated for each of the 3 domains (motor symptoms at night, PD symptoms at night, 
and disturbed sleep) as well as a total score.  The PDSS-2 domain scores range from 0 to 
20 and the total score ranges from 0 to 60.  There is no imputation of missing responses.  
If one or more item scores are missing, the total score and respective domain score will 
not be calculated.
The primary efficacy variables will be the change from baseline to Week 26 in the NMSS 
and PDSS-2 total scores.  They will each be estimated using PROC MIXED and a mixed-
effect repeated measures model (MMRM) for the change from baseline to each scheduled 
visit.  The model will include the fixed effects of treatment, country and visit, with 
baseline score as a covariate, and the baseline score-by-visit interaction.  The unstructured 
covariance structure will be used to estimate the within subject variance-covariance 
structure and Satterthwaite's approximation will be used to estimate the denominator 
degrees of freedom.  If the model fails to converge, the first order autoregressive (AR[1]) 
covariance structure will be substituted.  If the model still fails to converge, the compound 
symmetry (CS) covariance structure will be substituted.  Type III sum-of-squares and 
least-square (LS) means will be used for statistical evaluations.  The LS mean and 95% 
confidence interval obtained from the model will be presented.  The primary comparison 
will be the contrast between LCIG and optimized medical treatment at the Week 26 Visit.  
The primary null and alternative hypotheses may be expressed as:
H0:  !LCIG = !OMT
HA:  !LCIG ≠ !OMT
Where μLCIG is the mean change from baseline to Week 26 for LCIG group in the NMSS 
(or PDSS-2) total score and μOMT is the mean change from baseline to Week 26 for OMT 
group in the NMSS (or PDSS-2) total score.  The statistical tests at other visits will be 
considered secondary.
The change in the NMSS (or PDSS-2) total score to each planned visit and to the final 
visit will also be summarized by the following descriptive statistics:  number of non-


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missing observations, mean baseline score and standard deviation, mean visit score and 
standard deviation, median visit score and range, mean change from baseline and its 
standard deviation and standard error, median change from baseline and range.  The 
hypothesis of change from baseline will be evaluated at each visit with a one-sample 
t-test.
The two-sided P values obtained from the MMRM model for NMSS total score change 
from baseline to Week 26 and PDSS-2 total score change from baseline to Week 26 will 
be adjusted for multiplicity using the Hochberg procedure.  This method controls the 
family-wise error rate (FWER) at a pre-specified significance level (alpha = 0.05).  
Specifically, the following steps will be followed:
●
If the larger of the 2 P values is ≤ 0.05 (i.e., both P values are ≤ 0.05), both 
primary endpoints are considered statistically significant.
●
If the larger of the 2 P value is > 0.05, then compare the smaller P value with 
0.025.  The second primary endpoint is statistically significant if the P value is 
≤ 0.025; otherwise, neither primary endpoint is considered statistically 
significant.
The mean NMSS and PDSS-2 total scores at baseline, Week 6, Week 12 and Week 26 
and the mean changes in NMSS and PDSS-2 total scores from baseline to Week 6, 
Week 12 and Week 26 will be summarized by domain.  Each mean domain score as well 
as the percentage it represents of the NMSS and PDSS-2 total score will be presented.
9.3
Additional Efficacy Analyses
Secondary Analysis of the Primary Efficacy Variables
Analysis of covariance (ANCOVA) analyses will be carried out on change from baseline 
to final NMSS total score and change from baseline to final PDSS-2 total score.  The 
ANCOVA model will contain treatment and country as the main effects and baseline 
score as the covariate.  Sensitivity analyses will be carried out on the above variables with 
the same ANCOVA model using all randomized subjects.  In this analysis, Baseline 


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Observation Carried Forward (BLOCF) will be applied to subjects who do not have 
post-randomization assessment of NMSS or PDSS-2.
Analysis of Secondary Efficacy Variables
The MMRM model, and the descriptive statistic summary described for the NMSS and 
PDSS-2 total score will also be used to evaluate the change from baseline in each of the 
following efficacy endpoints:
●
UPDRS Part II score
●
Parkinson's Disease Questionnaire-8 (PDQ-8) summary index
●
NMSS domain scores
●
PDSS-2 domain scores
●
UPDRS total score, Part I score, Part III score, Part IV score
●
Parkinson Anxiety Scale (PAS) total and subscale scores
●
Geriatric Depression Scale (GDS-15)
●
King's PD Pain Scale total and domain scores
For CGI-C and PGIC, an analysis of variance (ANOVA) model containing treatment and 
country as the main effects will be carried out.
UPDRS Part II score, CGI-C score and PDQ-8 summary index are key secondary 
endpoints.  If both primary efficacy variables are statistically significant after adjusting for 
multiplicity, the Stepwise Gatekeeping Procedure will be utilized and the 3 key secondary 
endpoints will be tested using the Hochberg procedure with significance level of 0.05.  
Specifically, the following steps will be followed:
●
If the largest of the 3 P values is ≤ 0.05 (i.e., all 3 P values are ≤ 0.05), all 
3 key secondary endpoints are considered statistically significant.
●
If the largest of the 3 P value is > 0.05, then compare the middle P value with 
0.025.  The second and third key secondary endpoints are both statistically 
significant if the middle P value is ≤ 0.025.


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●
If the largest of the 3 P value is > 0.05 and the middle P value is > 0.025, then 
compare the smallest P value with 0.0167.  If the smallest P value is ≤ 0.0167, 
then the third key secondary endpoint is statistically significant.  Otherwise, 
none of the 3 key secondary endpoints can be considered statistically 
significant.
All secondary efficacy variables will be summarized by the number of subjects with non-
missing data, mean, standard deviation, median, minimum and maximum.  CGI-C and 
PGIC variables will also be summarized by the number of subjects with non-missing data 
and the number and percentage of subjects in each response category.  In addition, the 
summary of the PGIC will also include the number and percentage of subjects reporting 
improvement (response of either "very much improved," "much improved," or "minimally 
improved").
9.4
Calculation of Efficacy and Health Outcome Variable
The primary and secondary efficacy variables derived from the above measures are 
presented in Table 7. 


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Table 7.
Primary and Secondary Efficacy Variables, and Derivations
Instrument
Efficacy Variable
Derivation
Range/Direction
NMSS: 30 questions, 9 domains (cardiovascular/falls, 
sleep/fatigue, mood/cognition, perceptual 
problems/hallucinations, attention/memory, GI tract, 
urinary, sexual function, miscellaneous). 
Score of each question is calculated by multiplying 
severity•frequency.  Severity and frequency are rated 
using a scale ranging from 0 (none) to 3 (severe) for 
severity and from 1 (rarely) to 4 (very frequent) for 
frequency.  There is no imputation of missing 
responses.  If one or more item scores are missing, the 
total score and respective domain score will not be 
calculated.
Cardiovascular/falls
Sum of Questions 1 – 2
0 – 24/lower value desirable
Sleep/fatigue
Sum of Questions 3 – 6
0 – 48/lower value desirable
Mood/cognition
Sum of Questions 7 – 12
0 – 72/lower value desirable
Perceptual problems/hallucinations
Sum of Questions 13 – 15
0 – 36/lower value desirable
Attention/memory
Sum of Questions 16 – 18
0 – 36/lower value desirable
GI tract
Sum of Questions 19 – 21
0 – 36/lower value desirable
Urinary
Sum of Questions 22 – 24
0 – 36/lower value desirable
Sexual function
Sum of Questions 25 – 26
0 – 24/lower value desirable
Miscellaneous
Sum of Questions 27 – 30
0 – 48/lower value desirable
Total score
Addition of 9 domains
0 – 360/lower value desirable
PDSS-2:  15 questions, 3 domains.  Score of each 
question is based on a 5-point Likert-type scale 
(ranging from 0 [never] to 4 [very often]). There is no 
imputation of missing responses.  If one or more item 
scores are missing, the total score and respective 
domain score will not be calculated.
motor symptoms at night
Sum of Questions 1 – 5
0 – 20/lower value desirable
PD symptoms at night
Sum of Questions 6 – 10
0 – 20/lower value desirable
disturbed sleep
Sum of Questions 11 – 15
0 – 20/lower value desirable
Total score
Addition of 3 domains
0 – 60/lower value desirable


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Table 7.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
UPDRS:  42 questions, Part I (Questions 1 – 4), Part II 
(Questions 5 – 17), Part III (Questions 18 – 31), and 
Part IV (Questions 32 – 42).  Questions 35 – 38 and 
40 – 42 are 2-point (0 and 1), all other questions are 
5-point (0 – 4).
Part I score
Sum of Questions 1 – 4.  No missing 
answers will be imputed so Part I score will 
be missing if any of the answers are 
missing.
0 – 16/lower value desirable
Part II score
Sum of Questions 5 – 17.  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.
0 – 52/lower value desirable
Part III score
Sum of Questions 18 – 31 with 
Questions 20 – 26 apply to multiple body 
parts, resulting in 27 answers total.  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 III 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.
0 – 108/lower value desirable
Total score (Part I, II, III)
Sum of Part I, Part II, Part III scores.  Will 
be missing if any one of Part I, Part II, 
Part III scores is missing. 
0 – 176/lower value desirable


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Table 7.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
UPDRS:  42 questions, Part I (Questions 1 – 4), Part II 
(Questions 5 – 17), Part III (Questions 18 – 31), and 
Part IV (Questions 32 – 42).  Questions 35 – 38 and 
40 – 42 are 2-point (0 and 1), all other questions are 
5-point (0 – 4).  (continued)
Part IV score
Sum of Questions 32 – 42.  Part IV score 
will be calculated as long as at least 
10 answers have been recorded.  If 
1 answer is 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 to the 
number of answers provided.
0 – 23/lower value desirable
CGI-C:  7-point scale (1 = very much improved, 
2 = much improved, 3 = minimally improved, 4 = no 
change, 5 = minimally worse, 6 = much worse, 
7 = very much worse)
CGI-C score
7-point score as collected
1 – 7/lower score desirable
PDQ-8:  8 question including the mobility, activities 
of daily living, emotional well-being, stigma, social 
support, cognition, communication, bodily discomfort.  
5-point scale:  0 = Never, 1 = Occasionally, 
2 = Sometimes, 3 = Often, 4 = Always (or cannot do at 
all, if applicable).
PDQ-8 Summary Index (PDQ-SI)
Sum of each question divided by 32 and 
multiplied by 100.  The PDQ-8 total score 
will be calculated as long as at least 
7 questions have been answered.  Missing 
values in a question will be replaced by the 
patient population's mean of the question, 
and rounded to an integer.
0 – 100/lower value desirable
PGIC:  patient's opinion of degree of change since 
beginning care at the clinic, 7-point scale (1 = no 
change, 2 = almost the same, 3 = a little better, 
4 = somewhat better, 5 = moderately better, 6 = better, 
7 = a great deal better)
PGIC score
7-point score as collected
1 – 7/higher score desirable


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Table 7.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
King's PD Pain Scale:  14 items addressing the 
following 7 domains (musculoskeletal pain, Chronic 
pain, fluctuation-related pain, nocturnal pain, orofacial 
pain, neuropathic pain, radicular pain). 
Each item is scored by severity (0, none to 3, very 
severe) multiplied by frequency (0, never to 4, all the 
time) resulting in a subscore of 0 to 12, the sum of 
which gives the total score with a range from 0 to 168.
King's PD Pain score
Sum of 14 item scores.  The King's PD 
Pain Scale score will be calculated as long 
as at least 13 questions have been 
answered.  Missing values in a question 
will be replaced by the patient population's 
mean of the question, and rounded to an 
integer.
0 – 168/lower value desirable
PAS:  12-item including 1) Feeling anxious or nervous 
2) Feeling tense or stressed 3) Being unable to relax 
4) Excessive worrying about everyday matters 5) Fear 
of something bad, or even the worst, happening 
6) Panic or intense fear 7) Shortness of breath 8) Heart 
palpitations or heart beating fast 9) Fear of losing 
control 10) Social situations 11) Public settings 
12) Specific objects or situations Rated as:  0, Never; 
1 Rarely; 2, Sometimes; 3, Often; 4, Nearly always
PAS score
Sum of 12 item scores.  The PAS score 
will be calculated as long as at least 
11 questions have been answered.  
Missing values in a question will be 
replaced by the patient population's mean 
of the question, and rounded to an integer.
0 – 48/lower value desirable


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Table 7.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
GDS-15:  15 yes/no as following 1) satisfied with life 
2) Dropped many activities and interests 3) life is 
empty 4) Often get bored 5) In good spirits most of the 
time 6) Afraid that something bad is going to happen 
7) Feel happy most of the time 8) Often feel helpless 
9) Prefer to stay at home, rather than going out and 
doing things 10) Feel that have more problems with 
memory than most 11) Think it is wonderful to be alive 
now 12) Feel worthless 13) Feel full of energy 
14) Situation is hopeless 15) Most subjects are better 
off. 
Answer YES to question 2.3.4.6.8.9.10.12.14.15 will 
be scored 1 point. 
Answer NO to questions 1.5.7.11.13 will be scored 
1 point.
GDS-15 score
Sum of 15 item scores.  The GDS-15 score 
will be calculated as long as at least 
13 questions have been answered.  
Missing values in a question will be 
replaced by the patient population's mean 
of the question, and rounded to an integer.
0 – 15/lower value desirable


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9.5
Handling of Multiplicity
The two-sided P values obtained from the MMRM model for NMSS total score change 
from baseline to Week 26 and PDSS-2 total score change from baseline to Week 26 will 
be adjusted for multiplicity using the Hochberg procedure.  This method controls the 
family-wise error rate (FWER) at a pre-specified significance level (alpha = 0.05).  
Specifically, the following steps will be followed:
●
If the larger of the 2 P values is ≤ 0.05 (i.e., both P values are ≤ 0.05), both 
endpoints are considered statistically significant.
●
If the larger of the 2 P value is > 0.05, then compare the smaller P value with 
0.025.  The second endpoint is statistically significant if the P value is ≤ 0.025; 
otherwise, neither endpoint is considered statistically significant.
If both primary efficacy variables are statistically significant after adjusting for 
multiplicity, the Stepwise Gatekeeping Procedure will be utilized and the 3 key secondary 
endpoints (UPDRS Part II score, CGI-C score and PDQ-8 summary index) will be tested 
using the Hochberg procedure with significance level of 0.05.  Specifically, the following 
steps will be followed:
●
If the largest of the 3 P values is ≤ 0.05 (i.e., all 3 P values are ≤ 0.05), all 
3 key secondary endpoints are considered statistically significant.
●
If the largest of the 3 P value is > 0.05, then compare the middle P value with 
0.025.  The second and third key secondary endpoints are both statistically 
significant if the middle P value is ≤ 0.025.
●
If the largest of the 3 P value is > 0.05 and the middle P value is > 0.025, then 
compare the smallest P value with 0.0167.  If the smallest P value is ≤ 0.0167, 
then the third key secondary endpoint is statistically significant.  Otherwise, 
none of the 3 key secondary endpoints can be considered statistically 
significant.


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9.6
Efficacy Subgroup Analysis
To determine if the following factors have an impact on the response to treatment, 
subgroup analyses will be conducted on the change from baseline to final visit on the 
NMSS total score and PDSS-2 total score:
●
Gender
●
Age category (< 65, ≥ 65)
●
Duration of Parkinson's disease (< 10 years, ≥ 10 years)
●
Total daily dose of levodopa (< 1250 mg, ≥1250 mg) at the end of initial 
LCIG titration for the LCIG group and in the first set of dosing diary for the 
OMT group
●
Number of anti-PD medications other than levodopa taken at any time during 
the week prior to randomization (0 or 1, 2 or more)
The subgroup analyses will be performed using an ANCOVA model contain treatment, 
country, and subgroup as main effects, treatment by subgroup interaction, and baseline 
score as the covariate.  The LS mean change for each stratum of the subgroup with 
associated 95% confidence interval will be presented.
The descriptive statistic summary described for the NMSS and PDSS-2 total scores will 
also be prepared for each subgroup stratum.
10.0
Safety Analysis
10.1
General Considerations
Unless noted otherwise, all safety analyses will be performed on the Safety Dataset.  
Treatment group differences in safety parameters are evaluated using two-sided test at the 
significance of 0.050.
Unless otherwise specified, treatment group differences in continuous safety variables 
(e.g., changes from baseline to final observation on laboratory test variables) will be 


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assessed using an ANOVA model with the term of treatment, and the treatment group 
differences in binary safety variables will be evaluated using a Fisher's exact test.
10.2
Analysis of Adverse Events
All adverse events will be coded using the most current version of the Medical Dictionary 
for Regulatory Activities (MedDRA).  Adverse events will be summarized by primary 
MedDRA system organ class (SOC) and preferred term (PT).  Subjects reporting more 
than one adverse event for a given PT will be counted only once for that term.  Subjects 
reporting more than one adverse event within an SOC will be counted only once for the 
SOC total.  Subjects reporting more than one adverse event will be counted only once in 
the overall adverse event total.  For summaries by SOC and PT, the SOCs will be 
presented in alphabetical order and the PTs will be presented in alphabetical order within 
each SOC.
A treatment-emergent adverse event (TEAE) during the 26-week randomized treatment 
period is defined as:
●
For subjects in OMT group who don't continue into Extension Period:  any 
adverse event that begins or worsens in severity the day after randomization 
and within 30 days following the last visit. 
●
For subjects in OMT group and continue into Extension Period:  any adverse 
event that begins or worsens in severity the day after randomization and within 
30 days following the last visit during 26-week randomized treatment period 
or before the insertion of NJ/PEG-J (whichever is earlier). 
●
For LCIG treatment subjects who have all study tubes removed after their last 
study drug infusion, this includes all adverse events with onset on or after the 
date of the initial tube placement procedure and no more than 30 days 
following the last study tube removal, or no more than 30 days following the 
last LCIG infusion if there is no final device removal during the 26-week 
randomized treatment period.


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A TEAE during Extension Period for OMT subjects will be defined as any adverse event 
that begins or worsens in severity after the NJ or PEG-J placement through 30 days after 
last LCIG infusion or final device removal (whichever is later).
A TEAE during the continuing LCIG treatment period will be defined as any adverse 
event in LCIG group that begins or worsens in severity after Week 26 visit through 
30 days after last LCIG infusion or final device removal (whichever is later).
10.2.1
Adverse Event Overview
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories during the 26-week Treatment Period and during the 
Extension/Transition Period will be summarized.
●
Any TEAE
●
Any TEAE that was rated by the investigator as having a reasonable possibility 
of relationship to levodopa-carbidopa intestinal gel
●
Any severe TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
●
Any treatment emergent GI event (as defined in Section 10.2.3)
●
Any TEAE other than a GI event (as defined in Section 10.2.3)
●
A fatal TEAE
●
All deaths
Serious adverse events with onset during the Screening Period for all subjects screened, 
adverse events and serious adverse events with onset after day of randomization and 
before day of initial device placement for the LCIG group, as well as adverse events 
during the transition period for LCIG subjects continuing LCIG commercial treatment 
will also be summarized.


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10.2.2
Adverse Event Incidence
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories during the 26-week Treatment Period will be 
summarized for each treatment group and for overall subjects by primary SOC and PT. 
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
The percentage of subjects in the LCIG group and in the OMT group will be compared 
using Fisher's exact test.  Only P values ≤ 0.100 when rounded to three digits will be 
presented.
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories during the Extension/Transition Period will be 
summarized for OMT/LCIG subjects who enter the Extension/Transition Period by 
primary SOC and PT.
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug
The number and percentage of subjects experiencing one or more TEAEs during the 
26-week Treatment Period will also be summarized for each treatment group and for 
overall subjects by maximum severity category (mild, moderate, severe, or unknown) and 
primary SOC and PT.  Subjects reporting more than one TEAE for a given PT will be 
counted only once for that term in the most severe category reported.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 
category of "unknown," even if the subject has another occurrence of the same event with 
a severity present.  The only exception is if the subject has another occurrence of the same 


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adverse event with the most extreme severity – "Severe."  In this case, the subject will be 
counted under the "Severe" category.
The number and percentage of subjects experiencing one or more TEAEs during the 
26-week Treatment Period will also be summarized for each treatment group and for 
overall subjects by maximum relationship category (reasonable possibility, no reasonable 
possibility, or unknown), as assessed by the investigator, and primary SOC and PT.  
Subjects reporting more than one TEAE for a given PT will be counted only once for that 
term in the most related category reported.  If a subject has an adverse event with 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same adverse event with a relationship assessment of "Reasonable Possibility."  In this 
case, the subject will be counted under the "Reasonable Possibility" category.
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories 26-week randomized treatment period will be 
summarized by PT.  The PTs will be presented by decreasing frequency overall.
●
Any TEAE
●
Any TEAE that was moderate or severe
A list of subject numbers associated with each PT will also be presented for all TEAEs.
10.2.3
Adverse Events of Special Interest
Adverse events of special interest (AESIs) will be composite events made up of TEAEs 
meeting the following MedDRA search strategies.
●
GI events will include the MedDRA preferred terms (PTs) in the GI and GI 
procedure related events Company MedDRA Query (CMQ 80000145).


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●
POLY events will include the PTs in either the Peripheral Neuropathy 
Standard MedDRA Query (SMQ 20000034) broad search or Guillain-Barre 
Syndrome SMQ (SMQ 20000131) broad search.
●
WEIGHT events will include the PTs in the Weight loss CMQ 
(CMQ 80000109).
For each AESI, the number and percentage of subjects experiencing one or more adverse 
events during the 26-week randomized Treatment Period will be summarized for each 
treatment group and for overall subjects by primary SOC and PT.  Similar summaries will 
be prepared for all TEAEs that are not GI events as well as for all TEAEs that are in either 
the Peripheral Neuropathy Standard MedDRA Query (SMQ 20000034) narrow search or 
Guillain-Barre Syndrome SMQ (SMQ 20000131) narrow search.
10.2.4
Adverse Events by Subgroup
The number and percentage of subjects in each of the following subgroups experiencing 
one or more TEAEs during 26-week randomized Treatment Period will be summarized 
for each treatment group and for overall subjects by primary SOC and PT.
●
Gender (male, female)
●
Age category (< 65 years, ≥ 65 years)
●
Baseline BMI category (< 25 kg/m2, ≥ 25 kg/m2)
●
Duration of Parkinson's disease (< 10 years, ≥ 10 years) 
10.2.5
Listings of Adverse Events
The following additional summaries of adverse events will be prepared.
●
Listing of all deaths for all subjects screened
●
Listing of all serious TEAEs
●
Listing of all TEAEs that led to discontinuation of study drug
●
Listing of all GI AESIs (as defined in Section 10.2.3)
●
Listing of all POLY AESIs (as defined in Section 10.2.3)


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●
Listing of all WEIGHT AESIs (as defined in Section 10.2.3)
10.3
Analysis of Laboratory Tests
Hematology variables include:  partial thromboplastin time (PTT), hematocrit, 
hemoglobin, international normalized ratio (INR), mean corpuscular hemoglobin 
(MCHC), mean corpuscular volume (MCV), platelet count, prothrombin time (PT), red 
blood cell (RBC) count, white blood cell (WBC) count and WBC differentials.
Chemistry variables include:  albumin, alkaline phosphatase, bicarbonate, total bilirubin, 
blood urea nitrogen (BUN), calcium, chloride, cholesterol, creatine phosphokinase (CPK), 
creatinine, gamma-glutamyl transpeptidase (GGT), glucose, lactate dehydrogenase 
(LDH), inorganic phosphorus, potassium, serum glutamic-oxaloacetic transaminase 
(SGOT/AST), serum glutamic pyruvic transaminase (SGPT/ALT), total protein, sodium, 
TSH, free T4, triglycerides and uric acid.
Urinalysis variables include:  blood, glucose, ketones, pH, protein, specific gravity, and 
the results of microscopic analysis.
Special laboratory variables include:  Vitamin B12, Vitamin B6, methylmalonic acid 
(MMA), folic acid and homocysteine levels.
10.3.1
Analysis of Mean Changes for Laboratory Tests
Analyses of mean change from baseline to each planned visit and to the minimum, 
maximum and final value during the 26-week randomized treatment period will be 
presented by treatment group for each continuous hematology, chemistry, urinalysis, and 
special laboratory variable.
For each change from baseline analysis, the following summary statistics for each 
treatment group will be presented:  sample size, baseline mean, visit mean, and the mean, 
standard deviation, and median of the change from baseline.  The baseline and visit means 
will be calculated for each visit for subjects who have both a baseline and visit value.  The 


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mean changes for the LCIG group and for the OMT group during the 26-week 
randomized treatment period will be compared using an ANOVA with treatment as the 
factor.  LS mean, standard error, 95% confidence interval and P value will be presented.
Analyses of mean change from the Extension/Transition Period baseline to each planned 
visit and to the minimum, maximum and final value during the Extension/Transition 
Period will be presented for each continuous hematology, chemistry, urinalysis, and 
special laboratory variable for OMT/LCIG subjects who enter the Extension/Transition 
Period.
10.3.2
Shifts Between Normal and Abnormal for Laboratory Tests
Laboratory observations will be categorized as normal, low, or high relative to the 
reference (normal) range associated with the laboratory that performed the assay.  For 
each hematology, chemistry, urinalysis and special laboratory variable with a reference 
range, shift tables will be prepared by treatment group for reference range category shifts 
from baseline to lowest, highest and final value during the 26-week randomized treatment 
period.  The tables will present:
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at any post-baseline visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at any post-baseline visit
●
The numbers and percentages of subjects with low or normal observations at 
baseline who have a high observation at the final visit 
●
The numbers and percentages of subjects with normal or high observations at 
baseline who have a low observations at the final visit
No comparisons of treatment groups will be performed.


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10.3.3
Potentially Clinically Significant (PCS) Laboratory Values
Criteria for potentially clinically significant (PCS) values have been predefined for 
selected laboratory variables as outlined in Appendix F.  For each variable, a summary of 
the number and percentage of subjects in each treatment group who have at least one post-
baseline observation during the 26-week randomized treatment period that meets the PCS 
criteria and is more extreme than their baseline value will be provided.  
A summary of the number and percentage of subjects who have at least one observation 
during the Extension/Transition Period that meets the PCS criteria and is more extreme 
than their Extension/Transition Period baseline value will be provided for OMT/LCIG 
subjects who enter the Extension/Transition Period.
A listing will also be prepared that will include, for each variable, all observations for 
each subject that met the PCS criteria for that variable at any time during the study.  No 
comparisons of treatment groups will be performed.
10.4
Analysis of Vital Signs and Weight
Vital sign variables include:  body temperature, pulse (sitting, standing and orthostatic), 
diastolic blood pressure (sitting, standing and orthostatic), and systolic blood pressure 
(sitting, standing and orthostatic).
Weight variables include:  weight and BMI.
Orthostatic variables will be calculated as the change from sitting to standing (standing 
measurement minus sitting measurement).
BMI will be calculated using height as measured during screening.
10.4.1
Vital Sign and Weight Mean Changes
Analyses of mean change from baseline to each planned visit beginning with Day 7 and to 
the minimum, maximum and final value during the 26-week randomized treatment period 
will be presented by treatment group for each vital sign and weight variable.  On the day 


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of the first LCIG infusion, orthostatic vital signs are to be collected at 0, 1, 2 and 3 hours 
post initial LCIG infusion start.  Analyses of the mean change from pre-infusion baseline 
(planned time 0) to each post-infusion hourly time point will be presented for each vital 
sign variable other than body temperature for the LCIG group and subjects in OMT group 
entering Extension Period.
For each change from baseline analysis, the following summary statistics for each 
treatment group will be presented:  sample size, baseline mean, visit (time point) mean, 
and the mean, standard deviation, and median of the change from baseline.  The baseline 
and visit (time point) means will be calculated for each visit (time point) for subjects who 
have both a baseline and visit (time point) value.  The mean changes during the 26-week 
randomized treatment period for the LCIG group and for the OMT group will be 
compared using an ANOVA with treatment as the factor.  LS mean, standard error, 95% 
confidence interval and P value will be presented.
Analyses of mean change from the Extension/Transition Period baseline to each planned 
visit and to the minimum, maximum and final value during the Extension/Transition 
Period will be presented for each vital sign and weight variable for OMT/LCIG subjects 
who enter the Extension/Transition Period.
10.4.2
Shifts in BMI Category
BMI values will be categorized as low (< 18.5 kg/m2), normal (18.5 kg/m2 to < 25 kg/m2), 
overweight (25 kg/m2 to < 30 kg/m2) or obese (≥ 30 kg/m2).  Shift tables will be prepared 
summarizing BMI category shifts from baseline to lowest, highest and final value during 
the 26-week randomized treatment period for each treatment group.  No comparisons of 
treatment groups will be performed.
10.4.3
Potentially Clinically Significant (PCS) Vital Sign and Weight 
Values
Criteria for PCS values have been predefined for selected vital sign and weight variables 
as outlined in Appendix F.  For each variable, a summary of the number and percentage of 


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subjects in each treatment group who have at least one post-baseline observation during 
the 26-week randomized treatment period that meets the PCS criteria and is more extreme 
than their baseline value will be provided.  
A summary of the number and percentage of subjects who have at least one observation 
during the Extension/Transition Period that meets the PCS criteria and is more extreme 
than their Extension/Transition Period baseline value will be provided for OMT/LCIG 
subjects who enter the Extension/Transition Period.
A listing will also be prepared that will include, for each variable, all observations for 
each subject that met the PCS criteria for that variable at any time during the study.  No 
comparisons of treatment groups will be performed.
10.5
Analysis of Electrocardiogram (ECG) Variables
Electrocardiogram (ECG) variables include:  heart rate (HR), PR interval, QRS interval, 
uncorrected QT interval, QT interval corrected for heart rate using Bazett's formula 
(QTcB) and QT interval corrected for heart rate using Fridericia's formula (QTcF).
QTcB and QTcF will be calculated for each uncorrected QT interval based on the 
following formulas:
●
Bazett's correction (QTcB):  
)
/
60
(
HR
QT
B
QTC
∀
●
Fridericia's correction (QTcF):  
3
)
/
60
(
HR
QT
F
QTC
∀
10.5.1
ECG Mean Changes
Analyses of mean change from baseline to each planned visit and to the minimum, 
maximum and final value during the 26-week Treatment Period will be presented by 
treatment group for each ECG variable.
For each change from baseline analysis, the following summary statistics for each 
treatment group will be presented:  sample size, baseline mean, visit mean, and the mean, 


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standard deviation, and median of the change from baseline.  The baseline and visit means 
will be calculated for each visit for subjects who have both a baseline and visit value.  The 
mean changes for the LCIG group and for the OMT group will be compared using an 
ANOVA with treatment as the factor.  LS mean, standard error, 95% confidence interval 
and P value will be presented.
Analyses of mean change from the Extension/Transition Period baseline to each planned 
visit and to the minimum, maximum and final value during the Extension/Transition 
Period will be presented for each ECG variable for OMT/LCIG subjects who enter the 
Extension/Transition Period.
10.5.2
Potentially Clinically Significant (PCS) ECG Values
Criteria for PCS values have been predefined for selected ECG variables as outlined in 
Appendix H.  For each variable, a summary of the number and percentage of subjects in 
each treatment group who have at least one post-baseline observation during the 26-week 
Treatment Period that meets the PCS criteria and is more extreme than their baseline 
value will be provided.  
A summary of the number and percentage of subjects who have at least one observation 
during the Extension/Transition Period that meets the PCS criteria and is more extreme 
than their Extension/Transition Period baseline value will be provided for OMT/LCIG 
subjects who enter the Extension/Transition Period.
A listing will also be prepared that will include, for each variable, all observations for 
each subject that met the PCS criteria for that variable at any time during the study.  No 
comparisons of treatment groups will be performed.
10.6
Analysis of Sleep Attack Questions
At Screening Visit 1, the sleep attack questions will collect history during the previous 
3 months.  At all other visits, the sleep attack questions will collect experience since the 
last visit.  Affirmative responses to the sleep attack questions will be summarized by 


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treatment for the study period on or before the date of randomization and for the study 
period on or after Day 1.
Each summary will include the number and percentage of subjects in each treatment 
group reporting a) 1 or more sleep attacks at any visit, b) 1 or more sleep attacks at any 
visit without sleepiness or drowsiness prior to sleep attack, and c) 1 or more sleep attacks 
at any visit with bad outcome during the 26-week Treatment Period.  The highest number 
of sleep attacks reported at any visit (1, 2, 3, more than 3) will also be summarized by the 
number and percentage of subjects in each treatment group with each count.
A listing will also be prepared that includes all subjects who reported 1 or more sleep 
attacks at any visit.
A summary of the number and percentage of subjects with one or more sleep attacks 
during the Extension/Transition Period will also be provided for LCIG subjects who enter 
the Transition Period. 
10.7
Analysis of Minnesota Impulsive Disorders Interview (MIDI)
The Minnesota Impulsive Disorders Interview (MIDI) will be administered to monitor for 
the development of intense impulsive behavior.  It includes the following modules:  
buying disorder, kleptomania, trichotillomania, intermittent explosive disorder, 
pyromania, pathological gambling and compulsive sexual behavior.  A subject's MIDI 
screen is positive for a module 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


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●
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
Positive screens on the MIDI will be summarized for the study period on or before the 
date of randomization and during the 26-week Treatment Period.  Each summary will 
include the number and percentage of subjects in each treatment group with a positive 
screen for each MIDI module as well as for any of the MIDI modules.
A summary of the number and percentage of subjects with a positive screen for each 
MIDI module as well as for any of the MIDI modules during the Extension/Transition 
Period will also be provided for OMT/LCIG subjects who enter the Extension/Transition 
Period.
A listing will also be prepared that includes all subjects with 1 or more positive screens 
for any of the MIDI modules.
10.8
Analysis of Columbia-Suicide Severity Rating Scale
(C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a systematically administered 
instrument developed to track suicidal adverse events across a treatment study.  At 
Screening Visit 1 the C-SSRS will be administered to collect lifetime history as well as 
experience during the past year.  At all other visits, the C-SSRS will collect experience 
since the last visit.  Affirmative responses on the C-SSRS will be summarized for the 
following study periods and reporting timeframes:  Screening:  Lifetime and Past year; 
before randomization:  Since last visit; and on or after Day 1:  Since last visit.
Each summary will include the number and percentage of subjects in each treatment 
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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 during the 26-week Treatment Period.  No 
comparisons of treatment groups will be performed.
A summary of the number and percentage of subjects with one or more affirmative 
responses to the questions listed above during the Extension/Transition Period will also be 
provided for OMT/LCIG subjects who enter the Extension/Transition Period. 
A listing will also be prepared that includes all subjects with 1 or more affirmative 
responses.
11.0
Special Statistical Topics
There are no special statistical issues to be described or addressed.
12.0
Summary of Changes
This SAP contains no change in analysis from the latest version of the protocol 
(Protocol Amendment 4).
The changes in this SAP from SAP V1.0 is:  Per protocol amendments, subjects from   
South Korean/United States who complete the 26-week clinical study will have the option 
to enter an extension of the study.  This SAP added the description for Extension Period 
analyses. 
13.0
Appendices


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Appendix A.
Study Activities
OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Visit Number for OMT/LCIG
V1
V2c
(Optional)
V3
V4d
V5
V6
V7
V8
V9
Every 6 
and 
12 Weeks
Informed Consente
X
Medical/Neurological/PD Historyf
X
Concomitant Medication (including 
anti-PD and NMS medications)
X
X
X
X
X
X
X
X
X
X
Anti-PD Medication History
X
NMS Medication Historyg
X
MMSE (Mini-Mental State 
Examination)
X
Sleep Attacks Questionnaire
X
X
X
X
X
X
X
X
Physical Examinationh
X
X
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
X
Dermatological Examh
X
X
GI Examh
X
NJ or PEG-J decision 
X
Nasojejunal Tube Placement/Titrationi
(Optional)
X
PEG-J Placement Procedurej
X


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OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Radiological Check of Tube Placementj
X
PEG-J Site (Stoma) Check
Xk
X
X
X
X
X
X
Vital Signsl/Weight
X
X
X
X
X
X
X
X
X
X
Heightm
X
ECG
X
X
X
Clinical Labsn (+ urinalysis)n
X
X
Xn
X
X
Urine Drug/Alcohol Screen
X
X
Special Laboratory Testso
X
X
X
X
X
Pregnancy Testp
X
X
X
MIDI (Minnesota Impulsive Disorders 
Interview)
X
X
X
X
X
X
X
X
X
C-SSRSq
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Product Complaints
X
X
X
X
X
X
X
X
NMSS (Non-Motor Symptom Scale)
X
X
X
X
PDSS-2 (Modified Parkinson's Disease 
Sleep Scale)
X
X
X
X
UPDRS Parts I – Vr
X
X
X
X
X
CGI-C (Clinical Global Impression of 
Change)
X
PGIC
X


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OMT/LCIG
LCIG
OMT/LCIG
LCIG
OMT/LCIG
LCIG
Study Day
(End of Week)
V1
Screening
Wk –8/–4
V2
Screening
Wk –1
V3
Randomization
V4
NJ/PEG-J 
Placement 
D1
Titration 
Visits
Wk 
2
Wk 
6
Wk 
12
Wk 
17
Wk 
22
Wk 26 or 
Premature 
Discontinuation
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
PDQ-8 (Parkinson's Disease 
Questionnaire-8)
X
X
X
X
MoCA (Montreal Cognitive 
Assessment)
X
X
X
X
PAS (Parkinson Anxiety Scale)
X
X
X
X
GDS-15 (Geriatric Depression Scale)
X
X
X
X
King's PD Pain Scale
X
X
X
X
Dose Titration Diarys
X
Subject Dosing/Diary Completion
X
X
X
X
X
LCIG System and Pump Training 
(Subject and Caregiver)
X
X
OMT and LCIG Administration
X
X
X
X
X
X
LCIG Titration
X
X
X
X
X
X
X
X
Study Drug Prescription Record (LCIG 
group only)
X
X
X
X
X
X
X
Removal of PEG-J
Xt
LCIG Cassettes Dispensed and/or 
Returned
X
X
X
X
X
X
X
Xu
X
V = Visit; D = Day; FU = Follow-Up; Wk = Week
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG. 
b.
Applicable only to LCIG subjects who complete LCIG study treatment and will transition to commercial LCIG.  Subjects will return every 6 weeks to return used LCIG 
cassettes and be dispensed cassettes.  Safety assessments will be completed every 12 weeks until subjects' transition to commercial LCIG.


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c.
Visit 2 is optional and is based on the Investigator's discretion of individual subject need during stabilization of anti-PD medications and medications to treat NMS.
d.
Visit 4 for LCIG Treatment (LCIGT) group only.
e.
Study-related assessments, procedures or activities may not occur prior to subject completing signed informed consent process. 
f.
Update Medical/Neurological/PD History with any findings from Labs, Dermatologists, etc.
g.
NMS Medication History is to be collected at V1.  These include but are not limited to medications used for the treatment of the 9 NMS domains of experience of 
cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, GI tract, urinary, sexual function, and miscellaneous (pain, 
taste/smell, weight change, excessive sweating) should be collected.
h.
At Screening Visit 1 and 2 and Randomization Visit 3 a full physical examination will be performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.  On or prior to Visit 2, the Investigator and GI/surgeon or interventional radiologist, or their designated qualified personnel will thoroughly evaluate the subject's risk of 
undergoing PEG-J procedure.  The dermatological exam will be performed prior to Visit 2.  If a suspicious lesion is present, a biopsy should be obtained for proper diagnosis 
and confirmation that lesion does not meet exclusion criteria.
i.
For subjects randomized to LCIG, a temporary NJ tube may be used to optimize the dose of LCIG before treatment with a PEG-J is started.  The NJ test phase should not last 
longer than 7 days.  Following the NJ test phase, a PEG-J will be performed by a gastroenterologist proceduralist or surgeon.  Total time to titration via NJ and PEG-J should 
not exceed 14 days.  Alternatively, subjects may proceed directly to placement of PEG-J if deemed appropriate by investigator.  The number of days to titrate will vary for 
each subject.
j.
LCIG group only.  Radiological check of NJ and PEG-J to determine correct location should occur prior to LCIG infusion initiation and prior to restart of LCIG post PEG-J 
placement.  Placement can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
k.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG.
l.
On the day of the first LCIG infusion, orthostatic vital signs should be obtained at 0, 1, 2 and 3 hours post initial LCIG start.  An attempt should be made to obtain all other 
vital signs at a consistent time of day.  Vital signs should be repeated when PEG-J inserted.
m.
Height will be measured at Visit 1 only.
n.
PT/PTT will be performed at Screening Visits 1 and 3.  In the event the PT/PTT result at V3 is abnormal the subject should not proceed with the NJ and/or PEG-J placement 
and should contact the medical monitor.
o.
Special labs to detect vitamin deficiencies, listed in protocol amendment table 4, will be performed at the times indicated in Protocol Amendment Table 3.  If at any time 
during the study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is 
appropriate for further evaluation of polyneuropathy symptoms.  Thyroid function tests will be done at Screening Visit 1 only.
p.
All females of childbearing potential must have a serum pregnancy test performed at Screening Visit 1 and Premature Discontinuation/End of Study.  Additional testing may 
be required per local regulations.  A negative urine pregnancy test result is required prior to the NJ and/or PEG-J placement procedure and any radiological procedures.


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q.
The "Baseline/Screening" C-SSRS will be the first assessment scale administered to the subject.  At each subsequent visit, the "Since Last Visit" C-SSRS scale should be 
administered.
r.
At V1, the UPDRS Part III is conducted in the on/off state, all other times in the on state.  During Visit 1 the UPDRS Part III will be done during practically defined "Off" 
time and best "On" time.  The practically defined "Off" time UPDRS will be done in the morning prior to the subject taking their first daily dose of anti-PD medication.  At a 
minimum a subject should be 8 hours without anti-PD medication before the UPDRS is completed.  The best "On" time rating should be done approximately 1 to 2 hours post 
any morning dose of study drug or PD medications but prior to lunch.  If possible, the UPDRS should be done at the same time of day throughout the trial.  The "Off" time 
UPDRS will only be done during Screening; at all other times a complete UPDRS (Parts I through V) will be done during "On" time.
s.
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a tool to achieve dose optimization.  In the event it is used it should be completed 
hourly until the dose is optimized and then once AM and once PM it will be completed until the subject is discharged.  All adjustments can be recorded on the Dose Titration 
Diary allowing the Investigator to appropriately adjust, if needed, the following day's morning dose, continuous infusion rate and extra dose until the subject is optimized.
t.
PEG-J removal will be complete 1 week before follow up visit.
u.
At Week 27 follow up visit LCIG cassettes return only.
Note:
All applicable clinical, safety, health outcome and cognition assessments will be administered only by individuals qualified by the Sponsor.


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Appendix B.
Study Activities For South Korea Subjects Entering the Extension Period from the OMT Arm
Study Day 
(End of Week)
V8 
W26
V9 
NJ/PEG-J 
Placement "D1"
Titration 
Visits
+ W2
+ W6
+ M3
+ M6
Every 6 Months or 
Premature 
Discontinuation
FUa
Visit Number 
V8
V9d
V10
V11
V12
V13
V14 +
Concomitant Medication (including anti-PD and 
NMS medications)
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
Dermatological Examb
X
Xd
GI Examb
X
NJ or PEG-J decision 
X
Nasojejunal Tube Placement/Titrationc (Optional)
X
PEG-J Placement Proceduree
X
Radiological Check of Tube Placemente
X
PEG-J Site (Stoma) Check
Xg
X
X
X
X
X
X
X
Vital Signsf/Weight
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
Clinical Labs (+ urinalysis)
X
X
X
X
Special Laboratory Testsh
X
X
X
X
Pregnancy Testi
X
X
X
X
X
X
Visit Number 
V8
V9d
V10
V11
V12
V13
V14 +
C-SSRS
X
X
X
X
X
X
X
X


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Study Day 
(End of Week)
V8 
W26
V9 
NJ/PEG-J 
Placement "D1"
Titration 
Visits
+ W2
+ W6
+ M3
+ M6
Every 6 Months or 
Premature 
Discontinuation
FUa
MIDI
X
X
X
X
X
X
X
X
SAQ
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Product Complaints
X
X
X
X
X
X
X
X
Dose Titration Diaryj
X
Subject Dosing/Diary Completion
X
X
X
X
X
X
LCIG System and Pump Training (Subject and 
Caregiver)
X
LCIG Administration
X
X
X
X
X
X
X
LCIG Titration
X
X
X
X
X
X
X
Study Drug Prescription Record 
X
X
X
X
X
X
X
Removal of PEG-J
Xk
LCIG Cassettes Dispensed and/or Returned
X
X
X
X
X
X
Xl
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG.  
b.
On or prior to Visit 9, the Investigator and GI/surgeon or interventional radiologist, or their designated qualified personnel will thoroughly evaluate the subject's risk of 
undergoing PEG-J procedure.  The dermatological exam will be performed prior to Visit 9.  If a suspicious lesion is present, a biopsy should be obtained for proper diagnosis 
and confirmation that lesion does not meet exclusion criteria.
c.
A temporary NJ tube may be used to optimize the dose of LCIG before treatment with a PEG-J is started.  The NJ test phase should not last longer than 7 days.  Following the 
NJ test phase, a PEG-J will be performed by a gastroenterologist proceduralist or surgeon.  Total time to titration via NJ and PEG-J should not exceed 14 days.  Alternatively, 
subjects may proceed directly to placement of PEG-J if deemed appropriate by investigator.  The number of days to titrate will vary for each subject.
d.
End of study or premature discontinuation only.


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e.
Radiological check of NJ and PEG-J to determine correct location should occur prior to LCIG infusion initiation and prior to restart of LCIG post PEG-J placement.  
Placement can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
f.
On the day of the first LCIG infusion, orthostatic vital signs should be obtained at 0, 1, 2 and 3 hours post initial LCIG start.  An attempt should be made to obtain all other 
vital signs at a consistent time of day.  Vital signs should be repeated when PEG-J inserted.
g.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG.
h.
Special labs to detect vitamin deficiencies, listed in protocol-amendment4-02-us Table 6, will be performed at the times indicated in above table.  If at any time during the 
study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is appropriate for 
further evaluation of polyneuropathy symptoms. 
i.
Pregnancy Testing WOCBP must have a negative urine pregnancy test at NJ/PEG-J Placement "D1."  Monthly pregnancy testing should be performed during treatment, 
including at the last dose and until 5 × the half-life of the AbbVie product.
j.
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a tool to achieve dose optimization.  In the event it is used it should be completed 
hourly until the dose is optimized and then once AM and once PM it will be completed until the subject is discharged.  All adjustments can be recorded on the Dose Titration 
Diary allowing the Investigator to appropriately adjust, if needed, the following day's morning dose, continuous infusion rate and extra dose until the subject is optimized.
k.
PEG-J removal will be complete 1 week before follow up visit.
l.
At follow up visit LCIG cassettes return only.


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Appendix C.
Study Activities For South Korea Subjects Entering the Extension Period from the LCIG Arm
Study Day 
(End of Week)
V8 
W26
Every 6 Months 
Premature Discontinuation
FUa
Visit Number for OMT/LCIG
V8
V9+
Concomitant Medication (including anti-PD and NMS medications)
X
X
X
Physical Examination
X
X
X
Neurological Exam
X
X
X
Dermatological Exam
X
Xb
PEG-J Site (Stoma) Check
X
X
X
Vital Signs/Weight
X
X
X
ECG
X
X
Clinical Labs (+ urinalysis)
X
X
Special Laboratory Testsc
X
X
Pregnancy Testd
X
X
C-SSRS
X
X
X
MIDI
X
X
X
SAQ
X
X
X
Adverse Events
X
X
X
Product Complaints
X
X
X
Subject Dosing/Diary Completion
X
X
LCIG Administration
X
X
LCIG Titration
X
X


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Study Day 
(End of Week)
V8 
W26
Every 6 Months 
Premature Discontinuation
FUa
Study Drug Prescription Record 
X
X
Visit Number for OMT/LCIG
V8
V9+
Removal of PEG-J
Xe
LCIG Cassettes Dispensed and/or Returned
X
X
Xf
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG.  
b.
End of study or premature discontinuation only.
c.
Special labs to detect vitamin deficiencies, listed in in protocol-amendment4-02-sk Table 6, will be performed at the times indicated in above table.  If at any time during the 
study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is appropriate for 
further evaluation of polyneuropathy symptoms. 
d.
Pregnancy Testing WOCBP must have a negative urine pregnancy test at NJ/PEG-J Placement "D1."  Monthly pregnancy testing should be performed during treatment, 
including at the last dose and until 5 × the half-life of the AbbVie product.
e.
PEG-J removal will be complete 1 week before follow up visit.
f.
At follow up visit LCIG cassettes return only.


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Appendix D.
Study Activities For United States Subjects Entering Part 2 from the OMT Arm
Study Day 
(End of Week)
V8 
W26
V9 
NJ/PEG-J 
Placement "D1"
Titration 
Visits
+ W2
+ W6
+ M3
+ 6M/Premature 
Discontinuation
FUa
Visit Number 
V8
V9
V10
V11
V12
V13
Concomitant Medication (including anti-PD and NMS 
medications)
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
Dermatological Examb
X
Xd
GI Examb
X
NJ or PEG-J decision 
X
Nasojejunal Tube Placement/Titrationc (Optional)
X
PEG-J Placement Proceduree
X
Radiological Check of Tube Placemente
X
PEG-J Site (Stoma) Check
Xg
X
X
X
X
X
X
Vital Signsf/Weight
X
X
X
X
X
X
X
X
ECG
X
X
X
Clinical Labs (+ urinalysis)
X
X
X
Special Laboratory Testsh
X
X
X
Pregnancy Testi
X
X
X
X
X
Visit Number 
V8
V9
V10
V11
V12
V14
C-SSRS
X
X
X
X
X
X
X


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Study Day 
(End of Week)
V8 
W26
V9 
NJ/PEG-J 
Placement "D1"
Titration 
Visits
+ W2
+ W6
+ M3
+ 6M/Premature 
Discontinuation
FUa
Visit Number 
V8
V9
V10
V11
V12
V13
MIDI
X
X
X
X
X
X
X
SAQ
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Product Complaints
X
X
X
X
X
X
X
Dose Titration Diaryj
X
Subject Dosing/Diary Completion
X
X
X
X
X
LCIG System and Pump Training (Subject and 
Caregiver)
X
LCIG Administration
X
X
X
X
X
X
LCIG Titration
X
X
X
X
X
X
Study Drug Prescription Record 
X
X
X
X
X
X
Removal of PEG-J
Xk
LCIG Cassettes Dispensed and/or Returned
X
X
X
X
X
Xl
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG.  
b.
On or prior to Visit 9, the Investigator and GI/surgeon or interventional radiologist, or their designated qualified personnel will thoroughly evaluate the subject's risk of 
undergoing PEG-J procedure.  The dermatological exam will be performed prior to Visit 9.  If a suspicious lesion is present, a biopsy should be obtained for proper diagnosis 
and confirmation that lesion does not meet exclusion criteria.
c.
A temporary NJ tube may be used to optimize the dose of LCIG before treatment with a PEG-J is started.  The NJ test phase should not last longer than 7 days.  Following the 
NJ test phase, a PEG-J will be performed by a gastroenterologist proceduralist or surgeon.  Total time to titration via NJ and PEG-J should not exceed 14 days.  Alternatively, 
subjects may proceed directly to placement of PEG-J if deemed appropriate by investigator.  The number of days to titrate will vary for each subject.
d.
End of study or premature discontinuation only.


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e.
Radiological check of NJ and PEG-J to determine correct location should occur prior to LCIG infusion initiation and prior to restart of LCIG post PEG-J placement.  
Placement can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
f.
On the day of the first LCIG infusion, orthostatic vital signs should be obtained at 0, 1, 2 and 3 hours post initial LCIG start.  An attempt should be made to obtain all other 
vital signs at a consistent time of day.  Vital signs should be repeated when PEG-J inserted.
g.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG.
h.
Special labs to detect vitamin deficiencies, listed in protocol-amendment4-02-us Table 6, will be performed at the times indicated in above table.  If at any time during the 
study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is appropriate for 
further evaluation of polyneuropathy symptoms. 
i.
Pregnancy Testing WOCBP must have a negative urine pregnancy test at NJ/PEG-J Placement "D1."  Monthly pregnancy testing should be performed during treatment, 
including at the last dose and until 5 × the half-life of the AbbVie product.
j.
While the subject is in the hospital, the study staff may use the Dose Titration Diary as a tool to achieve dose optimization.  In the event it is used it should be completed 
hourly until the dose is optimized and then once AM and once PM it will be completed until the subject is discharged.  All adjustments can be recorded on the Dose Titration 
Diary allowing the Investigator to appropriately adjust, if needed, the following day's morning dose, continuous infusion rate and extra dose until the subject is optimized.
k.
PEG-J removal will be complete 1 week before follow up visit.
l.
At follow up visit LCIG cassettes return only.


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Appendix E.
Study Activities For United States Subjects Entering the Extension Period from the LCIG Arm
Study Day 
(End of Week)
W26
+ 3M
+ 6M/Premature 
Discontinuation
FUa
Visit Number for OMT/LCIG
V8
V9
V10
Concomitant Medication (including anti-PD and NMS medications)
X
X
X
X
Physical Examination
X
X
X
X
Neurological Exam
X
X
X
X
Dermatological Exam
X
Xb
PEG-J Site (Stoma) Check
X
X
X
X
Vital Signs/Weight
X
X
X
X
ECG
X
X
X
Clinical Labs (+ urinalysis)
X
X
X
Special Laboratory Testsc
X
X
X
Pregnancy Testd
X
X
X
C-SSRS
X
X
X
X
MIDI
X
X
X
X
SAQ
X
X
X
X
Adverse Events
X
X
X
X
Product Complaints
X
X
X
X
Subject Dosing/Diary Completion
X
X
X
LCIG Administration
X
X
X
LCIG Titration
X
X
X


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Version 2.0 – 11 Apr 2018
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Study Day 
(End of Week)
W26
+ 3M
+ 6M/Premature 
Discontinuation
FUa
Study Drug Prescription Record 
X
X
X
Visit Number for OMT/LCIG
V8
V9
V10
Removal of PEG-J
Xe
LCIG Cassettes Dispensed and/or Returned
X
X
X
Xf
a.
Applicable only to LCIG subjects who prematurely discontinue LCIG treatment, or complete LCIG study treatment but will not transition to commercial LCIG.  
b.
End of study or premature discontinuation only.
c.
Special labs to detect vitamin deficiencies, listed in protocol-amendment4-02-us Table 6, will be performed at the times indicated in above table.  If at any time during the 
study a subject displays symptoms of polyneuropathy, the Investigator must perform this lab panel and any other assessment that the Investigator feels is appropriate for 
further evaluation of polyneuropathy symptoms. 
d.
Pregnancy Testing WOCBP must have a negative urine pregnancy test at NJ/PEG-J Placement "D1."  Monthly pregnancy testing should be performed during treatment, 
including at the last dose and until 5 × the half-life of the AbbVie product.
e.
PEG-J removal will be complete 1 week before follow up visit.
f.
At follow up visit LCIG cassettes return only.


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Version 2.0 – 11 Apr 2018
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Appendix F.
Potentially Clinically Significant Laboratory Values
Clinical Laboratory Tests
Very Low (VL)
Very High (VH)
Hematology
Activated partial thromboplastin 
time (aPPT)
NA
> ULN
Hemoglobin
< 100 g/L (6.2 mmol/L)
> 40 g/L above ULN
Prothrombin Intl. Normalized 
Ratio (INR)
NA
> ULN
Lymphocyte 
< 0.5 × 109/L
> 20 × 109/L
Neutrophil 
< 1 × 109/L
NA
Platelets 
< 75 × 109/L
NA
White blood cell
< 2 × 109/L
> 100 × 109/L
Chemistry
Bilirubin
NA
> 1.5 × ULN
Cholesterol
NA
> 12.92 mmol/L (500 mg/dL)
Creatinine
NA
> 1.5 × ULN
Calcium (corrected serum)
< 1.75 mmol/L (7.0 mg/dL)
> 3.1 mmol/L (12.5 mg/dL)
Gamma-glutamyl transpeptidase 
(GGT)
NA
> 2.5 × ULN
Glucose (fasting)
< 2.2 mmol/L (40 mg/dL)
> 13.9 mmol/L (250 mg/dL)
Potassium
< 3.0 mmol/L
> 6.0 mmol/L
Triglycerides
NA
> 5.7 mmol/L (500 mg/dL)
Uric Acid
NA
> 0.59 mmol/L (10 mg/dL)
Albumin
< 20 g/L
NA
Sodium
< 130 mmol/L
> 155 mmol/L
Magnesium
< 0.4 mmol/L (0.9 mg/dL)
> 1.23 mmol/L (3.0 mg/dL)
Phosphate 
< 0.6 mmol/L (2.0 mg/dL)
NA
Enzymes
Alanine aminotransferase (ALT)
NA
> 3 × ULN
Alkaline phosphatase
NA
> 2.5 × ULN
Aspartate aminotransferase (AST)
NA
> 3 × ULN
Creatine Phosphokinase (CPK)
NA
> 5 × ULN


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Version 2.0 – 11 Apr 2018
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Appendix G.
Criteria for Potentially Clinically Significant Vital Sign and Weight 
Values
Vital Signs
Unit
Very Low (VL)
Very High (VH)
Systolic blood pressure 
(supine and standing)
mmHg
≤ 90 and decreased 
> 30 from baseline
≥ 180 and increased 
> 40 from baseline
Orthostatic systolic 
blood pressure 
mmHg
Decrease ≥ 30 from 
supine to standing
NA
Diastolic blood pressure 
(supine and standing)
mmHg
≤ 50 and decreased 
> 30 from baseline
≥ 105 and increased 
> 30 from baseline
Orthostatic diastolic 
blood pressure
mmHg
Decrease ≥ 20 from 
supine to standing
NA
Pulse rate
bpm
≤ 50 and decreased 
> 30 from baseline
≥ 120 and increased 
> 30 from baseline
Temperature (C)
degrees C
NA
≥ 38.3 and increase 
≥1.1 from baseline
Weight (kg)
kg
Decreased ≥ 7% from 
baseline
Increased ≥ 7% from 
baseline


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Version 2.0 – 11 Apr 2018
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Appendix H.
Criteria for Potentially Clinically Significant ECG Values
ECG Parameters
Unit
Very Low (VL)
Very High (VH)
Heart rate
bpm
≤ 50 and decreased 
> 30 from baseline
≥ 120 and increased 
> 30 from baseline
PQ/PR
ms
≤ 120
≥ 220
QTcB interval 
ms
NA
≥ 480
Increased ≥ 60 from baseline
QTcF Interval
ms
NA
≥ 480
Increased ≥ 60 from baseline