Conditions: Parkinson's Disease (PD)
Keywords: Carbidopa Levodopa Efficacy Levodopa-carbidopa intestinal gel Advanced Parkinson's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
The primary objective of this study was to examine the effect of levodopa-carbidopa intestinal gel (LCIG) compared with optimized medical treatment (OMT) on dyskinesia in participants with advanced Parkinson's disease (PD).

Detailed description:
This was a Phase 3b, open-label, randomized, multicenter, 12-week study. The study consisted of 3 sequential periods: Screening, Treatment, and Follow-Up. The OMT group had the same schedule of visits/procedures throughout the study as the LCIG treatment group, except for visits related to nasojejunal (NJ)/percutaneous endoscopic gastrostomy (PEG) procedures, titration of LCIG, and follow-up period.

Arms:
arm 1: Participants randomized to OMT continued their current anti Parkinson's disease (anti-PD) medication regimen for the duration of the study. All anti-PD medications and medications to treat dyskinesia must have remained stable for the duration of the study unless adjustments were medically indicated. The Investigator provided the prescription for continued OMT. arm 2: The total daily dose of infusion LCIG was composed of three components: (i) the morning dose, (ii) continuous maintenance infusion dose and (iii) extra doses. A temporary nasojejunal (NJ) tube may have been used initially with the infusion pump to determine a participant's response to this method of treatment and to optimize the dose of LCIG before treatment with a permanent percutaneous endoscopic gastrostomy - with jejunal extension (PEG-J) tube was started. Following optional NJ and/or PEG-J placement and, at the investigator's discretion, the participant may have begun initiation and titration of LCIG infusion on Day 1 once tube placement was confirmed. The dose of LCIG was adjusted to obtain the optimal clinical response. The rate of LCIG infusion is typically within the range of 1 to 10 mL/hour (20 to 200 mg of levodopa/hour) in most instances and runs over a period of 16 consecutive hours each day.

Interventions: intervention 1: Optimized antiparkinsonian treatment intervention 2: Levodopa-Carbidopa Intestinal Gel (LCIG) intervention 3: CADD-Legacy ambulatory infusion pump intervention 4: Percutaneous endoscopic gastrostomy tube intervention 5: Jejunal extension tube
Intervention descriptions: intervention 1: Dose levels of prescribed antiparkinsonian medications were individually optimized to their maximum therapeutic effect. intervention 2: Dose levels were individually optimized. intervention 3: (manufactured by Smiths Medical) intervention 4: (PEG tube) intervention 5: (J-tube)

Protocol document:
Prot_000.pdf: 
Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
1
1.0
Title Page
Clinical Study Protocol M15-535
An Open-label, Randomized 12 Week Study 
Comparing Efficacy of Levodopa-Carbidopa 
Intestinal Gel/Carbidopa-Levodopa Enteral 
Suspension and Optimized Medical Treatment on 
Dyskinesia in Subjects with Advanced Parkinson's 
Disease
DYSCOVER (DYSkinesia COmparative interventional 
trial on Duodopa VERsus oral medication)
Incorporating Amendment 1
AbbVie Investigational
  Product:
Levodopa-Carbidopa Intestinal Gel (LCIG)/Carbidopa Levodopa Enteral 
Suspension (CLES)
Date:
26 May 2016
Development Phase:
3b
Study Design:
A Phase 3b, open-label, multicenter, 12 week study comparing LCIG/CLES 
to Optimized Medical Treatment (OMT) on dyskinesia associated with 
advanced Parkinson's disease.  
EudraCT Number:
2016-001403-23
Investigators:
Investigators information on file at AbbVie
Sponsor:
AbbVie
NCT02799381


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
2
Sponsor/Emergency 
  Contact:
 MD
AbbVie
1 North Waukegan Road
North Chicago, IL 60064-6145
Phone:
Mobile:
Fax:
The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
3
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
03 May 2016
The purpose of this amendment is to:
●
Change the study duration from 26 weeks to 12 weeks.
Rationale:  
 
 
 
 
 
●
Remove the exclusion criterion for excluding patients previously treated with 
continuous subcutaneous apomorphine infusion.
Rationale: 
 
●
Add language for additional analysis to provide evidence on the construct 
validity of the UDysRS.
Rationale: 
 
 
 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-535
Name of Study Drug:  Levodopa-Carbidopa 
Intestinal Gel (Outside United States)/Carbidopa-
Levodopa Enteral Suspension (United States)
Phase of Development:  3b
Name of Active Ingredient:
Levodopa-Carbidopa Intestinal Gel (OUS)/ 
Carbidopa-Levodopa Enteral Suspension (US)
Date of Protocol Synopsis:  26 May 2016
Protocol Title:  An Open-label, Randomized 12 Week Study Comparing Efficacy of Levodopa-
Carbidopa Intestinal Gel/Carbidopa-Levodopa Enteral Suspension and Optimized Medical Treatment on 
Dyskinesia in Subjects with Advanced Parkinson's Disease
DYSCOVER (DYSkinesia COmparative interventional trial on Duodopa VERsus oral medication)
Rationale and Background:
The rationale to conduct this open-label, interventional study is to investigate the comparative 
effectiveness of Levodopa-Carbidopa Intestinal Gel (LCIG)/Carbidopa-Levodopa Enteral Suspension 
(CLES) versus optimized medical treatment on the duration and severity of dyskinesia.  LCIG is 
marketed as Duopa in the US and as Duodopa in most other countries.  Optimized medical treatment 
(OMT) 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.
Dyskinesias are among the most troublesome symptoms of Advanced Parkinson's Disease (APD):  
Approximately 50% of patients present with Dyskinesia 4 – 5 years after initiation of treatment; 
approximately 90% of patients after 9 years.
Peak-dose dyskinesia are linked to peak plasma levels of levodopa, while the less frequent and 
phenomenologically different biphasic dyskinesia occur during switch from low to high plasma levels 
and vice versa.  Moderate to severe dyskinesia can be painful and disabling, compromising quality of 
life.  Therefore dyskinesia is one of the main reasons for recommending invasive treatments in APD 
patients. 
Levodopa-Carbidopa Intestinal Gel (LCIG)/Carbidopa-Levodopa Enteral Suspension (CLES) is a stable 
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.  In contrast to oral therapy, 
LCIG/CLES provides continuous dopaminergic delivery which is believed to stimulate the dopaminergic 
receptors in the brain within the individual's therapeutic window resulting in decreased motor 
fluctuations and dyskinesia.  Over the past years many clinical investigations have been performed and 
published demonstrating that functional ON time during the day is increased, OFF time and ON time 
with disabling dyskinesia are reduced with a marked effect on quality of life (Olanow et al 2014, 
Slevin et al 2015, Fernandez et al 2015).


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
5
Rationale and Background (Continued):
Interventional studies (Studies S187-3-001/S187-3-002, S187-3-004, Antonini et al 2013) and 
observational studies (GLORIA, Poewe et al 2015) suggests that LCIG/CLES may decrease duration and 
severity of dyskinesia in studies of up to 2 years in duration.  This will be the first large interventional 
controlled study of LCIG for Advanced Parkinson's Disease patients specifically investigating the 
effectiveness on dyskinesia.
* Duodopa/Duopa will be referred to as Levodopa-Carbidopa Intestinal Gel (LCIG) throughout this 
protocol.  In the US, the product name is Duopa (Carbidopa Levodopa Enteral Suspension (CLES)).
Objectives:  
Primary:  The primary objective of this interventional study is to examine the effect of LCIG treatment 
relative to that of optimized medical treatment (OMT) on dyskinesia as measured by the change from 
baseline to Week 12 in the Unified Dyskinesia Rating Scale (UDysRS) Total Score.
Secondary:  To assess the effect of LCIG treatment  relative to that of OMT on dyskinesia as measured 
by PD Diaries, motor and non-motor symptoms, motor complications, safety, tolerability and health-
related outcome measures.
Motor Symptoms/Motor Complications and Non-Motor Symptoms Will Be Measured by:
!
Unified Dyskinesia Rating Scale (UDysRS)
!
Parkinson's Disease Diary (PD Diary) normalized average daily hours of OFF time, ON time 
with troublesome dyskinesia, ON time without troublesome dyskinesia
!
Unified Parkinson's Disease Rating Scale (UPDRS) Part III
!
Modified Abnormal Involuntary Movement Scale (mAIMS) 
Health Related Outcomes Will Be Measured by:
!
UPDRS Part II
!
Parkinson's Disease Questionnaire-8 (PDQ-8)
!
King's PD Pain Scale
!
Clinical Global Impression of  Severity (CGI-S)
!
Clinical Global Impression of Change (CGI-C)
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)
Investigators:  Multi-center
Study Sites:  This study will be conducted at approximately 22 – 28 sites that specialize in movement 
disorders in approximately 6 – 8 countries (WEC, EEMEA, USA) where LCIG is commercially 
available.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
6
Study Population:  Levodopa-responsive advanced 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:  A total of approximately 60 subjects with advanced PD will be 
enrolled (approximately 30 per treatment group).
Methodology:  
This is an open-label, randomized multicenter 12 week study comparing LCIG treatment to 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 treatment group, except 
for visits related to NJ/PEG procedures, titration of LCIG and follow-up period.
Patients, who in collaboration with their physicians at participating centers, have been found eligible for 
inclusion into this study in a screening visit will be enrolled into this study. 
The treatment goal is to achieve 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.
Figure 1:  Study Design Schematic
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any 
reason.  7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.
  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
7
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.  Results from lab samples collected at V3 will 
only be used as baseline level and are not intended to determine eligibility for randomization.  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 
dyskinesia.  All anti-PD medications, including those used to treat dyskinesia, must be stable with no 
adjustments to the frequency of administration, dose of administration or total daily dose for a minimum 
of 30 consecutive days before the randomization visit.  During the Screening Period, no study drug 
(LCIG) will be administered.  Visit 2 is optional and is based on the Investigator's discretion of 
individual subject need during stabilization of anti-PD medications.  Subjects who are deemed eligible 
by randomization criteria at Visit 3 will be randomized after all planned assessments have been 
completed to receive LCIG treatment or to continue on OMT.
Treatment Period (V4 – V8)
Those subjects randomized to continue OMT will remain on their current optimized regimen and will 
have study visits at the end of Weeks 2, 4, 8, and 12 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, anti-PD medications should remain stable and 
changes can only be made if medically indicated.
A stable regimen is defined as no changes to the frequency of administration, dose of administration or 
total daily dose.  Those subjects randomized to LCIG treatment must discontinue all other anti-PD 
medications except amantadine (e.g., dopamine agonists, COMT-inhibitors, MAO-B inhibitors, anti-
cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG treatment initiation on Day 1 (V4); 
these medications should be tapered off according to their individual package insert, and at the discretion 
of the Investigator, over a period of up to 14 days.  With the exception of apomorphine, levodopa 
containing formulations or amantadine (see next paragraph), these medications may be restarted if 
indicated by the subject's individual condition, but not within the first 28 days after PEG placement 
procedure.
As an exception, subjects in both groups who take amantadine at the randomization visit (V3) must not 
discontinue this treatment and are required to continue this treatment for the entire study duration with 
the regimen kept stable unless the Investigator decides that it is medically indicated to discontinue this 
treatment.  If subjects do not take amantadine at the Visit 1 (Screening Visit 1), this treatment must not 
be initiated during the entire study duration.
For those subjects randomized to LCIG treatment, 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, surgeon 
or interventional radiologist.  Total time on 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 Investigator.  If the subject proceeds directly to PEG-J, titration should be 
completed within 7 days.  However, at the Investigator's discretion additional days of optimization may 
be used if clinically indicated.  Subjects on LCIG treatment will return for study visits at the end of 
Weeks 2, 4, 8, and 12 and following PEG-J placement.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
8
Methodology (Continued):
Treatment Period (V4 – V8) (Continued)
If a subject is prematurely discontinued for any reason, the Week 12 procedures and assessments will be 
completed.
Study Follow-Up
The OMT subjects will not have a follow-up visit (V9).
For LCIG treatment subjects who elect to discontinue LCIG treatment and not continue with 
commercially available product, a V9 will be conducted one week after PEG-J removal and the SAE/AE 
follow-up period will be up until 30 days after PEG-J removal.  For LCIG treatment subjects who will 
transition to commercial product, the SAE/AE follow-up period will be up until 30 days after the 
transition.
For all study visits apart from V1 to V3 a ± 3 days visit window will be allowed.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Subject must be able to understand the nature of the study and has had the opportunity to have any 
questions answered by the Investigator. 
2.
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 Investigator to have decision making 
capacity, must have voluntarily signed the Independent Ethics Committees/Institutional Review 
Board (IEC/IRB) approved Informed Consent. 
3.
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.
4.
Male or female subjects of at least 30 years old at the time of Visit 3.
5.
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 Brain 
Bank Criteria.
6.
Patients with advanced levodopa-responsive Parkinson's disease and persistent motor fluctuations 
who have not been controlled with optimized medical treatment.  "Optimized medical treatment" is 
defined as the maximum therapeutic effect obtained with pharmacological antiparkinsonian 
therapies when no further improvement is expected with regard to any additional manipulations of 
levodopa and/or other antiparkinsonian medication.  This will be based on the Investigator's clinical 
judgment.
7.
UDysRS Total score ≥ 30 at Visit 3 based on Central Blinded Rater's score.
8.
Subject must demonstrate at least 75% concordance with the Investigator's or qualified designee's 
assessment of symptoms on the Parkinson's Disease Diary following training at Screening Visit 1 
with concordance on at least 1 time interval of "Off," concordance on at least 1 time interval of "ON 
regardless of dyskinesia" and at least 1 time interval of "ON with dyskinesia" irrespective of whether 
the dyskinesia are troublesome or not troublesome.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
9.
Subject (or subject's proxy/caregiver) must be able to complete both the Subject Dosing Diary and 
the PD Diary and must be able to demonstrate the ability to operate, manipulate, and care for the 
pump and tubing.
10. Subject is eligible to transfer to commercial treatment of Duodopa after completing the study based 
on local country requirements.
Main Exclusion:
1.
Predominantly di-phasic dyskinesia, as per Investigator discretion.
2.
Patients who were treated with LCIG before.
3.
Patients who have had previous surgery for PD including, but not limited to deep brain stimulation 
(DBS) or cell transplantation.
4.
Participation in a concurrent interventional or observational study.
5.
Lack of motivation or insufficient language skills to complete the study questionnaires
6.
Subject experiencing clinically significant sleep attacks or clinically significant impulsive behavior 
(e.g., pathological gambling, hypersexuality) at any point during the 3 months prior to the 
Screening evaluation as judged by the Investigator.
7.
Current diagnosis or history of drug or alcohol abuse (DSM-V-TR criteria) within 12 months prior 
to screening visit.
8.
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).
9.
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), atypical Parkinson Syndrome (e.g., Multiple System Atrophy, 
Progressive supranuclear Palsy, Diffuse Lewy Body disease) or other neurodegenerative disease 
that might mimic the symptoms of PD.
10. A Mini-Mental State Examination (MMSE) score < 24 at Visit 1 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/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
10
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.
Doses:
LCIG:  For those randomized to LCIG treatment, each subject's dose 
will be individually optimized in accordance with the LCIG approved 
product label for countries participating in the study. 
Treatment goal is to achieve a balanced improvement of both OFF time 
and dyskinesia according to physicians' judgment, optimal clinical 
response for the individual subject, 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 medically indicated.  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 approximately 
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:
Investigator discretion and/or in accordance with approved product 
label of the prescribed medications
Mode of Administration:
Oral, sub-lingual or transdermal
Duration of Treatment:  12 weeks
Criteria for Evaluation:
Efficacy:
Primary Efficacy Endpoint:
The primary efficacy variable will be the mean change from baseline to Week 12 in UDysRS Total 
Score.
The UDysRS was chosen for the assessment of the primary endpoint because it was developed 
specifically for the assessment of dyskinesia in PD and is endorsed by the International Parkinson and 
Movement Disorder Society [Goetz 2013].  Containing both self-evaluation questions by the subject 
alone and physician-assessed items to objectively rate dyskinesia and off-dystonia, its clinimetric 
properties are excellent [Goetz 2008] and it has been demonstrated to be superior for detecting treatment 
effects compared to other available dyskinesia scales [Goetz 2013].


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
11
Criteria for Evaluation (Continued):
Efficacy (Continued):
Secondary Endpoints (with hierarchical analysis)
!
ON time without troublesome dyskinesia as measured by the PD Diary
!
PDQ-8 Summary Index
!
CGI-C
!
UPDRS Part II  Score
!
OFF time as measured by PD Diary
!
UPDRS Part III  Score
Additional Efficacy Endpoints are: 
!
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
!
ON time with troublesome dyskinesia and ON time without dyskinesia as measured by PD 
Diary
!
mAIMS
Additional Health Outcome Endpoints are: 
!
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
!
Columbia Suicide Severity Rating Scale (C-SSRS)
!
Minnesota Impulsive Disorders Interview (MIDI)
!
Sleep Attacks Questionnaire(SAQ)
Statistical Methods:
Efficacy:
Efficacy Dataset and Treatment Period
The efficacy analysis will be performed on the intent-to-treat (ITT) dataset which will include all 
subjects who are randomized to the OMT, and all subjects who are randomized to LCIG treatment and 
received at least one dose of study drug following PEG-J placement.  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/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
12
Statistical Methods (Continued):
Efficacy (Continued):
Primary Efficacy Analysis
The primary efficacy variable is the change from baseline to Week 12 for UDysRS total score.  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 treatment and OMT at the 
Week 12 Visit.
Secondary Efficacy Analyses
The secondary efficacy variables are the mean change from baseline to Week 12 in the following 
measures:
!
ON time without troublesome dyskinesia as measured by the PD Diary
!
PDQ-8 summary index
!
CGI-C
!
UPDRS Part II Score
!
OFF time as measured by PD Diary.
!
UPDRS Part III  Score
Each secondary efficacy variable will be analyzed with the same MMRM model as the primary analysis.  
PD Diary variables will be the average time recorded by the subject on the 3 diaries prior to each visit 
after normalization to a 16 hour day.
If the primary efficacy variable is statistically significant, the secondary variables will be tested using the 
fixed sequence above as a gatekeeping procedure and an α level of 0.050.  Testing will cease at the point 
that a secondary variable fails to demonstrate statistical significance.
Additional Efficacy and Health Outcome Analyses
Efficacy will also be assessed using the following additional measures:
!
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
!
ON time with troublesome dyskinesia and ON time without dyskinesia as measured by PD 
Diary
!
mAIMS score
Health outcomes will also be assessed with the following additional measures: 
!
King's PD Pain Scale
Continuous endpoints will be analyzed with the same MMRM model as the primary analysis.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
13
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 OMT, and all subjects who are randomized to LCIG treatment and had a study device 
placement procedure.  For assessments of safety, the treatment period will begin the day after 
randomization for subjects randomized to OMT, and the day of initial study tube placement (NJ or 
PEG-J) for subjects randomized to LCIG.  The treatment period will end on the day of the final visit for 
subjects randomized to OMT.  For subjects randomized to LCIG, the treatment period will end on the 
day of the final study tube removal if all study tubes are removed on or after the last day of LCIG study 
drug infusion.  For all other subjects randomized to LCIG treatment, the treatment period will end on the 
day of the final visit.  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 Analyses
Safety analyses will include summaries of adverse events, clinical laboratory evaluations, vital signs and 
weight, special labs and the C-SSRS, and MIDI.  
Determination of Sample Size
Approximately 60 subjects will be enrolled into the study and randomized in a 1:1 ratio to either OMT or 
LCIG.  Subject randomization will be stratified by country.  A treatment group difference of 10 points is 
assumed for the mean change from baseline to Week 12 in the UDysRS total score based on results 
reported by Pahwa et al and a pooled standard deviation of 12 is assumed based on results reported by 
Goetz et al.  Assuming that the treatment group difference between LCIG and OMT groups is 10 points 
and the pooled standard deviation is 12, 27 subjects per group will have 85% power to detect a treatment 
group difference at a two-sided significance level of 0.050.  It is further assumed that 10% of 
randomized subjects in either treatment group will not provide post-randomization efficacy assessment.  
Therefore the total planned enrollment is decided to be approximately 60 subjects.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
14
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
β-HCG 
beta-human chorionic gonadotropin
BOCF
Baseline observation carried forward
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CGI-C
Clinical Global Impression – Change 
CGI-S
Clinical Global Impression – Severity 
CHMP
Committee for Medicinal Products for Human Use
CLES
Carbidopa Levodopa Enteral Suspension
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
DNS
Duodopa Nurse Specialist
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture
EQ VAS
EuroQol Visual Analogue Scale 
FDA
Food and Drug Administration


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
15
GCP
Good Clinical Practice
GDSM
Global Drug Supply Management
GI
Gastroenterologist
GMP
Good Manufacturing Practice
HCP
Health Care Professional
IB
Investigator's Brochure
ICC
Intra-class correlation coefficient
ICH
International Council 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
mAIMS
Modified Abnormal involuntary movement scale
MAO-A
monoamine oxidase A
MAO-B
monoamine oxidase B
MAO Inhibitors
monamine oxidase inhibitors
Max
Maximum
MD
Doctor of Medicine
MDS
Movement Disorder Society
MedDRA
Medical Dictionary for Regulatory Activities
MIDI
Minnesota Impulsive Disorders Interview
Min
Minimum
MMA
methylmalonic acid
MMSE
Mini-Mental State Examination
MMRM
Mixed-effect Model Repeated-Measures
NCS
Not Clinically Significant
NDC
National Drug Code


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
16
NJ
Nasojejunal
NMS
Neuroleptic Malignant Syndrome
NP
Nurse Practitioner
NONMEM®
nonlinear mixed effects modeling
3-OMD
3-O-methyldopa
OMT
Optimized Medical Treatment
OUS
Outside United States
PA
Physician Assistant
PC
Product Complaints
PCS
Potentially Clinically Significant 
PD
Parkinson's disease
PDQ-8
Parkinson's Disease Questionnaire-8
PEG
percutaneous endoscopic gastrostomy
PEG-J
percutaneous endoscopic gastrostomy – with jejunal extension
PhD
Doctor of Philosophy
PK
Pharmacokinetic
PT
preferred term
QoL
Quality of Life
REM
rapid eye movement 
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
SOC
system organ class
TA MD
Therapeutic Area Medical Director
UDysRS
Unified Dyskinesia Rating Scale 
UKPDS
United Kingdom Parkinson's Disease Society
UPDRS
Unified Parkinson's Disease Rating Scale
WHO
World Health Organization
WOCBP
Women Of Child Bearing Potential


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
17
Definition of Terms
Dose Titration Diary
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.
Duodopa Nurse 
Specialist*
An external nurse specialist which 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 Medical 
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 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.
Therapeutic Area Medical 
Director (TA MD)
Physician from AbbVie who is assigned in the protocol as the sponsor and 
emergency contact (also known as Study Designated Physician or Medical 
Monitor). 
*
Alternative titles for this function are as below:
AbbVie Duodopa Specialist (ADS)
Nurse Educator (NE)


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
18
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................14
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................23
3.1
Differences Statement..............................................................................30
3.2
Benefits and Risks....................................................................................30
4.0
Study Objective......................................................................34
5.0
Investigational Plan...............................................................35
5.1
Overall Study Design and Plan:  Description ..........................................35
5.1.1
Screening Period ......................................................................................36
5.1.2
The Treatment Period ..............................................................................39
5.1.2.1
OMT Group .............................................................................................39
5.1.2.2
LCIG Treatment Group............................................................................40
5.1.3
Study Follow-Up......................................................................................44
5.2
Selection of Study Population..................................................................45
5.2.1
Inclusion Criteria .....................................................................................45
5.2.2
Exclusion Criteria ....................................................................................47
5.2.3
Prior and Concomitant Therapy...............................................................51
5.2.3.1
Prior Therapy (Prior to Randomization) ..................................................51
5.2.3.2
Concomitant Therapy...............................................................................51
5.2.3.3
Rescue Therapy (LCIG Treatment Group Only) .....................................56
5.2.3.4
Post Infusion Night Time Therapy (LCIG Treatment Group Only) ........56
5.2.4
Contraception Recommendations and Pregnancy Testing.......................56
5.3
Efficacy and Safety Assessments/Variables ............................................58
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................58
5.3.1.1
Study Procedures .....................................................................................64
5.3.1.2
Rater Requirements..................................................................................81
5.3.1.3
Ancillary Support.....................................................................................82
5.3.2
Drug Concentration Measurements .........................................................83


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
19
5.3.3
Efficacy Variables....................................................................................83
5.3.3.1
Primary Efficacy Variable .......................................................................83
5.3.3.2
Additional Efficacy and Health Outcome Variables................................84
5.3.4
Safety Variables .......................................................................................84
5.4
Removal of Subjects from Therapy or Assessment .................................85
5.4.1
Discontinuation of Individual Subjects....................................................85
5.4.2
Removal of the PEG-J (LCIG Treatment Group Only)...........................86
5.4.3
Discontinuation of Entire Study...............................................................87
5.5
Treatments................................................................................................87
5.5.1
Treatments Administered.........................................................................87
5.5.1.1
OMT.........................................................................................................87
5.5.1.2
LCIG ........................................................................................................87
5.5.2
Identity of Investigational Product...........................................................93
5.5.2.1
Investigational Product and Supplies.......................................................93
5.5.2.2
Packaging and Labeling...........................................................................94
5.5.2.3
Storage and Disposition of Study Drugs..................................................95
5.5.3
Method of Assigning Subjects to Treatment Groups...............................95
5.5.4
Selection and Timing of Dose for Each Subject......................................96
5.5.5
Blinding....................................................................................................96
5.5.6
Treatment Compliance.............................................................................97
5.5.7
Drug Accountability.................................................................................97
5.5.8
Device Accountability .............................................................................98
5.6
Discussion and Justification of Study Design..........................................98
5.6.1
Discussion of Study Design and Choice of Control Groups....................98
5.6.2
Appropriateness of Measurements...........................................................99
5.6.3
Suitability of Subject Population ...........................................................101
5.6.4
Selection of Doses in the Study .............................................................101
6.0
Complaints ...........................................................................101
6.1
Medical Complaints...............................................................................102
6.2
Definitions..............................................................................................102
6.2.1
Adverse Event........................................................................................102
6.2.2
Serious Adverse Events .........................................................................103
6.2.3
Adverse Events of Special Interest ........................................................104


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
20
6.3
Adverse Event Severity..........................................................................105
6.4
Relationship to Study Drug....................................................................106
6.5
Adverse Event Collection Period...........................................................106
6.6
Adverse Event Reporting.......................................................................107
6.7
Pregnancy...............................................................................................109
6.8
Product Complaint .................................................................................109
6.8.1
Definition ...............................................................................................109
6.8.2
Reporting................................................................................................110
7.0
Protocol Deviations..............................................................110
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................111
8.1
Statistical and Analytical Plans..............................................................111
8.1.1
Analysis Datasets ...................................................................................111
8.1.2
Demographic, Other Baseline Characteristics, Subject 
Disposition, and Concomitant Medication ............................................112
8.1.3
Efficacy Analysis ...................................................................................114
8.1.3.1
Primary Efficacy Analysis .....................................................................114
8.1.3.2
Secondary Efficacy Analysis .................................................................115
8.1.3.3
Additional Efficacy and Health Outcomes Analyses.............................116
8.1.4
Safety Analysis ......................................................................................117
8.1.4.1
OMT and LCIG Treatment Exposure ....................................................117
8.1.4.2
Adverse Events ......................................................................................117
8.1.4.3
Clinical Laboratory Variables................................................................119
8.1.4.4
Vital Sign Variables and Weight ...........................................................119
8.1.4.5
ECG Variables .......................................................................................120
8.1.4.6
Additional Safety Variables...................................................................120
8.1.5
Interim Analysis.....................................................................................120
8.2
Determination of Sample Size ...............................................................121
8.3
Randomization Methods ........................................................................121
9.0
Ethics.....................................................................................121
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................121
9.2
Ethical Conduct of the Study .................................................................122


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
21
9.3
Subject Information and Consent...........................................................122
9.3.1
Informed Consent Form and Explanatory Material ...............................123
9.3.2
Revision of the Consent Form and Explanatory Material .....................123
10.0
Source Documents and Case Report Form 
Completion ...........................................................................123
10.1
Source Documents .................................................................................123
10.2
Case Report Forms.................................................................................124
11.0
Data Quality Assurance......................................................125
12.0
Use of Information...............................................................125
12.1
Subject Privacy ......................................................................................125
13.0
Completion of the Study .....................................................126
14.0
Investigator's Agreement....................................................127
15.0
Reference List ......................................................................128
List of Tables
Table 1.
UDysRS Sections.....................................................................................29
Table 2.
TEAEs Reported in ≥ 10% of Subjects by Descending Frequency 
(Open-Label LCIG Analysis Set) ............................................................33
Table 3.
Prohibited Medications and Treatments ..................................................55
Table 4.
Study Activities........................................................................................59
Table 5.
Clinical Laboratory Tests.........................................................................71
Table 6.
Study Drug...............................................................................................93
Table 7.
Investigational Devices Provided for Delivery of Drug ..........................94
Table 8.
UDysRS Sections.....................................................................................99
List of Figures
Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System..............................26
Figure 2.
Study Design Schematic ..........................................................................36
Figure 3.
Adverse Event Collection ......................................................................107


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
22
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................132
Appendix B.
List of Protocol Signatories....................................................................134
Appendix C.
UK Parkinson's Disease Society Brain Bank Clinical Diagnostic 
Criteria ...................................................................................................135
Appendix D.
Potentially Clinically Significant Laboratory Values for 
Study M15-535 ......................................................................................137
Appendix E.
Protocol Amendment:  List of Changes.................................................142


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
23
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 50% of patients after 4 to 5 years of treatment with levodopa 
and up to 90% of patients may experience motor fluctuations after 9 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 may still 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 apomorphine continuous 
infusion, 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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
24
been 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
Dyskinesia are among the most troublesome symptoms of Advanced Parkinson's Disease 
(APD):  approximately 50% of patients present with Dyskinesia 4 – 5 years after initiation 
of treatment; approximately 90% of patients after 9 years.
Peak-dose dyskinesia are linked to peak plasma levels of levodopa, while the less frequent 
and phenomenologically different biphasic dyskinesia occur during switch from low to 
high plasma levels and vice versa.  Moderate to severe dyskinesia can be painful and 
disabling, compromising quality of life.  Therefore dyskinesia is one of the main reasons 
for recommending invasive treatments in APD patients. 
Levodopa-Carbidopa Intestinal Gel (LCIG) is a stable 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.  In 
contrast to oral therapy, LCIG treatment provides continuous dopaminergic delivery 
which is believed to stimulate the dopaminergic receptors in the brain within the 
individual's therapeutic window resulting in decreased motor fluctuations and dyskinesia.  
Over the past years many clinical investigations have been performed and published 
demonstrating that functional ON time during the day is increased, OFF time is reduced 
and ON time without troublesome dyskinesia is increased with a marked effect on quality 
of life.16-18


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
25
Levodopa-Carbidopa Intestinal Gel (LCIG) treatment has been marketed for more than 
10 years in many countries.  The LCIG System is currently approved in 48 countries for 
the treatment of levodopa-responsive advanced PD.  In the majority of countries, it is 
marketed under the trade name Duodopa while in the US it is marketed as Duopa.  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 treatment 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 treatment reduces "Off" time and 
increases "On" time compared to oral levodopa-carbidopa.19  Some studies suggest that 
the improvement of LCIG infusion may be correlated with the severity of Parkinsonian 
symptoms while on oral treatment.20  The delivery of LCIG treatment 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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
26
Figure 1.
Levodopa-Carbidopa Intestinal Gel Infusion System
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 treatment 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 treatment 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%).21


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
27
Improvements were also seen with LCIG treatment in disease-specific and global Quality 
of Life (QoL) measures, as assessed by Clinical Global Impression-Improvement scale 
(CGI-I), Parkinson's Disease Questionnaire-Item (PDQ-8) summary index, and EuroQol 
Visual Analogue Scale (EQ VAS) scores.22
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 
(≥ 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.
LCIG treatment also has been shown to be effective in controlling troublesome 
Dyskinesia in patients with advanced Parkinson's disease.  Post hoc analyses of patient 
data from a 12-week, randomized, double-blind study and a 54-week open-label study 
were performed.  Efficacy was assessed in the subgroup of patients defined by at least 
1 hour of "on" time with troublesome dyskinesia at baseline as recorded in Parkinson's 
disease symptom diaries (double blind:  n = 11 levodopa-carbidopa intestinal gel, n = 12 
oral levodopa-carbidopa; open label:  n = 144 levodopa-carbidopa intestinal gel).  The 
changes in "off" time, "on" time with and without troublesome dyskinesia, and the overall 
safety and tolerability of LCIG were analyzed.  Although not significantly different from 
oral levodopa treatment (P > 0.05) in the double-blind study, levodopa-carbidopa 
intestinal gel treatment resulted in a reduction from baseline in "On" time with 
troublesome dyskinesia (mean [standard deviation] hours:  baseline = 3.1 [1.7], change 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
28
from baseline to final = –1.8 [1.8], P = 0.014), increase in "On" time without troublesome 
dyskinesia (baseline = 7.4 [2.2], change = 4.4 [3.6], P = 0.004), and decrease in "Off" time 
(baseline = 5.5 [1.3], change = –2.7 [2.8], P = 0.015).  Similar trends were found in the 
open-label study.  An increase in levodopa-carbidopa intestinal gel dose was not 
significantly correlated with increased "On" time with troublesome dyskinesia in either 
study (double blind:  r = –0.073, P = 0.842; open label:  r = –0.001, P = 0.992).  Adverse 
events were usually mild to moderate in severity and related to the gastrointestinal 
procedure.
When specifically evaluating the effect of LCIG treatment on dyskinesia in Parkinson's 
disease patients, no previous interventional studies have compared LCIG treatment to 
optimized medical treatment using the UDysRS as an endpoint.
UDysRS
The Unified Dyskinesia Rating Scale (UDysRS) is a rating tool specifically designed to 
assess dyskinesia in PD.  It is composed of modified versions of previously existing rating 
scales and in a comprehensive way assesses both the subjective and the objective aspects 
of the presence of dyskinesia.  Although relatively new, multiple clinical trials of new 
putative anti-dyskinesia agents are currently underway using UDysRS as the primary 
endpoint.  The UDysRS contains both self-evaluation questions (completed by the patient 
alone or with their caregivers) and items that are assessed directly by the physician to 
objectively rate the abnormal movements associated with PD.  The UDysRS contains 
four sections.  Two sections examine the historical disability of ON-dyskinesia (Part 1) 
and OFF-dystonia (Part 2) as perceived by the patient.  Two sections assess the objective 
impairment (Part 3) and disability (Part 4) caused by the dyskinesia during the time of 
assessment.  All parts consist of several items and each item is scored on a scale from 0 –
4 in a Likert model (0 = normal to 4 = severe) and the total score can range from 0 – 104.  
Table 1 lists the sections and corresponding parts of the UDysRS.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
29
Table 1.
UDysRS Sections
Section
Part
Completed by
Measure
Number 
of Items
Score 
Range
Historical 
disability
Part 1
Patient/Caregiver
Patient perception of on-dyskinesia 
impact
11 items
0 – 44
Part 2
Patient/Caregiver
Patient perception of off-dystonia 
impact
4 items
0 – 16
Objective
Part 3
HCP
Rating of dyskinesia (severity, 
anatomical distribution and type of 
dyskinesia (chorea, dystonia) based 
on HCP's observation of patients 
performing 4 motor tasks 
(communication, drinking, dressing 
ambulation)
7 items
0 – 28
Part 4
HCP
Disability scale rating based on 
HCP's observation of activities 
performed by patient in Part 3
4 items
0 – 16
UDysRS Validation and Psychometric Properties
The original development and validation study was conducted by Goetz et al (2008). 23  
Twenty international movement disorder experts participated in the study.  Internal 
consistency, factor structure and reproducibility of the scale were determined in 70 PD 
patients.  The UDysRS showed high internal consistency for both the subjective 
(Cronbach's alpha = 0.92) and objective rating sections (Cronbach's alpha = 0.97).  The 
scale demonstrated a very good level of inter-rater agreement for both, the summary score 
of impairment (ICC = 0.87) and the summary score of disability (ICC = 0.91).  The intra-
class correlation coefficient of the overall total objective score (sum of Parts 3 and 4 
scores) was 0.89.  Similarly, the scale demonstrated very good levels of intra-rater 
reliability.  The intra-class correlation coefficients for the intra-rater reliability were 0.91, 
0.84 and 0.90 for the total impairment, total disability and total objective score, 
respectively.  Repeated measures ANOVA was used to assess ability to detect change in 
UDysRS Parts 3 and 4; the UDysRS demonstrated an effect size = 0.138, with sensitivity 
to detect a treatment difference as small as 80% of a standard deviation (Goetz 2013).24  
Evidence is supportive of the ability of Parts 3 and 4 to detect change, however Parts 1 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
30
and 2 were not assessed.  Convergent and discriminant validity have also not been 
assessed.
In conclusion, the UDysRS, which has been endorsed by the Movement Disorder Society 
(MDS), is a comprehensive rating tool to measure dyskinesia and has been shown to be 
both a consistent and a reliable measure.
3.1
Differences Statement 
So far no prospective controlled data have been generated on the efficacy of LCIG on 
dyskinesia.  Preliminary evidence from post-hoc analyses from both interventional25 and 
observational studies suggests that LCIG may decrease duration and severity of 
dyskinesia for up to 2 years.25,26  This will be the first large interventional controlled study 
of LCIG for advanced Parkinson's disease patients specifically investigating the 
effectiveness on dyskinesia.
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 
infusion of the gel formulation, 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 treatment on motor symptoms in subjects with advanced PD has been 
demonstrated in Phase 3 studies.  In the pivotal Phase 3 study 
(Studies S187-3-001/S187-3-002), compared to LC-IR, LCIG treatment 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 treatment 
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
31
through better control of the motor fluctuations that are not adequately controlled with 
other PD medications.
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.27
Important Identified Risks
●
Gastrointestinal, Gastrointestinal Device, and Gastrointestinal Procedure 
Related Events
●
Dyskinesia
●
Psychosis Associated Events
●
Impulsive Control Disorders (ICDs)
●
Orthostatic Hypotension
●
Sudden Onset of Sleep/Somnolence
●
Neuroleptic Malignant Syndrome (NMS)
Adverse events of special interest (AESI) related to LCIG treatment, 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.  AESIs for this study are defined in Section 6.2.3 and comprise the following:
Known Risks
●
Gastrointestinal and Gastrointestinal Procedure Related Events
Potential Risks
●
Polyneuropathy
●
Weight Loss


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
32
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 2).  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 
representing mean treatment duration of 854 days (open-label LCIG analysis set) are in 
Table 2.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
33
Table 2.
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)
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
34
(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
The primary objective of this interventional study is to examine the effect of LCIG 
treatment relative to that of Optimized Medical Treatment (OMT) on dyskinesia as 
measured by the Unified Dyskinesia Rating Scale (UDysRS) Total Score.
The Secondary objective is to assess the effect of LCIG treatment relative to that of OMT 
on dyskinesia as measured by PD Diaries, motor symptoms, motor complications, health-
related outcome measures, safety and tolerability.
Motor Symptoms/Motor Complications Will Be Measured by:
●
Unified Dyskinesia Rating Scale (UDysRS)
●
Parkinson's Disease Diary (PD Diary):  normalized average daily hours of OFF 
time, ON time with troublesome dyskinesia, ON time without troublesome 
dyskinesia
●
Unified Parkinson's Disease Rating Scale (UPDRS) Part III
●
Modified Abnormal Involuntary Movement Scale (mAIMS) 
Health Related Outcomes Will Be Measured by:
●
UPDRS Part II
●
Parkinson's Disease Questionaire-8 (PDQ-8)
●
King's PD Pain Scale
●
Clinical Global Impression of Severity (CGI-S)
●
Clinical Global Impression of Change (CGI-C)
Safety and Tolerability Will Be Assessed by:
●
Adverse event monitoring


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
35
●
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)
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3b, open-label, randomized multicenter 12 week study assessing the 
efficacy of LCIG treatment compared to OMT on dyskinesia in subjects with Advanced 
Parkinson's Disease. 
This study will be conducted at approximately 22 – 28 sites that specialize in movement 
disorders in approximately 6 – 8 countries where LCIG is commercially available.
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 treatment group, except for visits related to NJ/PEG procedures, titration of LCIG 
and follow-up period.
Patients, who in collaboration with their physicians at participating centers have been 
found eligible for inclusion into this study during the screening period, will be enrolled 
into this study.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
36
Figure 2.
Study Design Schematic
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any reason.  
7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.
The study is designed to enroll an adequate number of subjects such that approximately 
60 subjects will be randomized in a 1:1 ratio to either treatment group of OMT or LCIG 
treatment in order to meet scientific and regulatory objectives without over-enrolling an 
undue number of subjects in alignment with ethical considerations.
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 will be between 30 – 67 days to accommodate the 
required procedures, training and collection of diaries, and allow for stabilization of 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
37
anti-PD medications and medications to treat dyskinesia.  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.  OMT 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.
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 4 of Section 5.3.1 for a detailed list of assessments and procedures and to 
Section 5.3.1.1 for detailed information on each procedure. 
●
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.  
For the OFF time rating the subject should be at a minimum of 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 Visit 1; all other UPDRS assessments will be 
done during "On" time.
●
The Investigator 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.
●
Parkinson's Disease Diary training and concordance testing: The subject and 
caregiver, if applicable, will be required to have a PD Diary training. 
Following this training, the subject will be given a PD Diary to be filled in 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
38
over a minimum period of 3 hours for a concordance evaluation on site.  
During this period, the subject must experience at least one transition from 
"Off" to "On" or from "On" to "Off," which must be observed by the 
Investigator.  The Investigator will also complete a separate PD Diary for this 
period.  There must be at least 75% concordance overall between the subject's 
Parkinson's Disease Diary and the Parkinson's Disease Diary completed by the
Investigator or Investigator's qualified designee including concordance on at 
least 1 time interval of "Off," concordance on at least 1 time interval of "On" 
regardless of dyskinesia and at least 1 time interval of "On with dyskinesia" 
irrespective of whether the dyskinesia are troublesome or not troublesome.  
The testing time can be extended in order to capture all required states.  If the 
concordance criteria are not met, the subject will undergo re-training of 
Parkinson's Disease Diary completion and repeat the concordance evaluation.  
If the concordance criteria are not met again the subject should be considered 
not-eligible for the study.
●
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, including those used to treat dyskinesia, must be 
stable with no adjustments to the frequency of administration, dose of 
administration or total daily dose for a minimum of 30 consecutive days before 
the randomization visit.
Optional Visit 2 (V2)
Visit 2 will occur between from 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, including those used to treat dyskinesia.  Subjects must be on stable anti-PD 
medications, including those used to treat dyskinesia, for at least 30 consecutive days 
before V3.  However, the time period between V1 and V2 must not exceed 60 days.  If, in 
the Investigator's opinion, it is medically necessary for the time frame between V1 and V2 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
39
to exceed 60 days, the Investigator should discuss this with the AbbVie TA MD (also 
known as Study Designated Physician or Medical Monitor).
Visit 3 (V3)
Visit 3 will be the randomization visit.  V3 assessments will be split over 2 days and both 
visits should occur within a maximum period of 1 week (7 days).  The UDysRS shall be 
administered and the videotape forwarded to the Central Blinded Rater on the first day of 
assessments.
The IRT randomization transaction should be made on the second day of V3 
randomization visit after the subject's eligibility has been confirmed.
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 UDysRS total score of 30 at Visit 3 as 
assessed by the Central Blinded Rater to qualify for randomization. 
Results from lab samples collected at V3 will only be used as baseline level and are not 
intended to determine eligibility for randomization.  
In addition at V3 the following should occur:
●
Training on the LCIG System and Pump will be initiated only for subjects 
randomized for LCIG treatment and their caregivers, as applicable.
5.1.2
The Treatment Period
For all study visits apart from V1 to V3 a ± 3 days visit window will be allowed.  
5.1.2.1
OMT Group
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 Investigator will provide the 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
40
prescription for continued OMT.  All anti-PD medications, including those to treat 
dyskinesia, must remain stable for the duration of the study unless medically indicated.  A 
stable regimen is defined as no changes to the frequency of administration, dose of 
administration or total daily dose.  If changes to anti-PD medications or medications to 
treat dyskinesia are needed, this should first be discussed with the AbbVie TA MD unless 
there is immediate safety concern.  The day after randomization will be considered Day 1 
of the treatment period for the OMT group.  Subjects in the OMT Group will not have a 
Visit 4.  Visits 5 through 8 will take place at the end of Weeks 2 through 12 respectively.  
If at any time a subject early terminates the study, all procedures related to Week 12 visit 
should be completed.  For all visits, the assessments will be completed as indicated in 
Table 4.
5.1.2.2
LCIG Treatment Group
Tapering of Anti-PD Medications Other Than Levodopa
Subjects randomized to LCIG treatment must discontinue all other anti-PD medications 
other than amantadine (e.g., dopamine agonists, COMT-inhibitors, MAO-B inhibitors, 
anti-cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG treatment initiation 
on Day 1 (V4); these medications should be tapered off within 14 days after 
randomization according to the discretion of the Investigator.  With the exception of 
apomorphine, levodopa containing formulations or amantadine (see next paragraph), these 
medications may be restarted if indicated by the subject's individual condition, but not 
within the first 28 days after LCIG treatment initiation.
As an exception, subjects in both OMT and LCIG groups who take amantadine at the 
randomization visit (V3) must not discontinue this treatment and are required to continue 
this treatment for the entire study duration with the regimen kept stable unless the 
Investigator decides that it is medically indicated to discontinue this treatment.  If subjects 
do not take amantadine at the Visit 1 (Screening Visit 1), this treatment must not be 
initiated during the entire study duration. 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
41
NJ and/or PEG-J Placement
LCIG treatment 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 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 (V4) by a gastroenterologist proceduralist, surgeon or interventional 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, surgeon or interventional radiologist as applicable 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 4).  The NJ tube will be removed 
at the time of the PEG-J procedure, or upon discontinuation of treatment with LCIG.  If 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
42
the subject does not enter the PEG-J placement procedure phase of the study, all 
End-of-Study Treatment/V8 (Week 12) procedures and assessments will be completed.
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 other than 
amantadine 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.
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 if required, at the discretion of the investigator or local practitioner, 
subjects may be admitted and remain hospitalized for the duration of the titration period.  
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 
inhibitor) tablets may be taken up to 2 hours (for oral LC-IR) or 4 hours (for oral LC-CR) 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
43
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.
During the titration, the subject (and if applicable, their caregiver) will receive 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 4.
The gastroenterologist proceduralist, surgeon or interventional radiologist as applicable 
will check the subject's stoma site within 24 hours and anytime from Day 2 to 7 after the 
PEG-J procedure.  The stoma check will be recorded on the appropriate eCRF.
Treatment:  Visit 5 (Week 2) Initial Post-PEG-J Evaluation Through Visit 8 
(Week 12)
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 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 end of 
Weeks 4, 8 and 12 respectively will be recorded on the appropriate eCRF and the 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
44
assessments completed as in Table 4.  If at any time a subject early terminates the study, 
all procedures related to Week 12 visit should be completed.
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.
5.1.3
Study Follow-Up
Follow-Up Visit (V9) (LCIG Treatment Subjects Not Continuing on Commercial 
Product)
For LCIG subjects who elect to discontinue LCIG and not continue with commercially 
available product, a V9 will be conducted 1 week after PEG-J removal and the SAE/AE 
follow-up period will be up until 30 days after PEG-J removal.
Commercial Transition Visits (LCIG Treatment Subjects Continuing on Commercial 
Product)
For LCIG treatment subjects who will transition to commercial product, the SAE/AE 
follow-up period will be up until 30 days after the transition.
Study subjects in the LCIG treatment 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 treatment until transition to commercial product is 
coordinated with the Sponsor's commercial affiliate.
Upon transfer of subjects to commercial LCIG treatment 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, following the 
30 day SAE/AE follow-up period, no formal collection of data will be conducted except 
for regular Adverse Drug Reaction (ADR) reporting in accordance with local instructions.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
45
OMT Subjects
The OMT subjects will not have a follow-up visit (V9).
Study subjects in the OMT group who complete participation in the study are eligible to 
transition to commercial LCIG treatment 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 be able to understand the nature of the study and has had the 
opportunity to have any questions answered by the Investigator. 
2.
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 Investigator 
to have decision making capacity, must have voluntarily signed the Independent 
Ethics Committees/Institutional Review Board (IEC/IRB) approved Informed 
Consent. 
3.
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.
4.
Male or female subjects of at least 30 years old at the time of Visit 3.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
46
5.
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.
6.
The subject's Parkinson's disease is levodopa-responsive.
7.
Patients with advanced levodopa-responsive Parkinson's disease and persistent 
motor fluctuations who have not been controlled with optimized medical treatment.  
"Optimized medical 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.
8.
UDysRS Total score ≥ 30 at Visit 3 based on Central Blinded Rater's score.
9.
Subject must demonstrate at least 75% concordance with the Investigator's or 
qualified designee's assessment of symptoms on the Parkinson's Disease Diary 
following training at Screening Visit 1 with concordance on at least 1 time interval 
of "Off," concordance on at least 1 time interval of "ON regardless of dyskinesia" 
and at least 1 time interval of "ON with dyskinesia" irrespective of whether the 
dyskinesia are troublesome or not troublesome.
10.
Subject (or subject's proxy/caregiver) must be able to complete both the Subject 
Dosing Diary and the PD Diary and must be able to demonstrate the ability to 
operate, manipulate, and care for the pump and tubing.
11.
Subject must have a 75% or greater compliance rate on the PD Diary completion at 
Visit 3.
12.
Subject is eligible to transfer to commercial treatment of Duodopa after completing 
the study based on local country requirements.
13.
For Female Subjects:
If female, subject must be either postmenopausal, OR permanently surgically 
sterile OR for Women of Childbearing Potential practicing at least one protocol 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
47
specified method of birth control (Section 5.2.4), starting at Study Day 1 through at 
least 30 days after the last dose of study drug. 
For Male Subjects:
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 (Section 5.2.4).
No male contraception is required.
14.
Females of childbearing potential must have a negative serum pregnancy test result 
at Visit 1, and a negative urine pregnancy test at Visit 3.
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined above) at Screening do not require pregnancy testing.
Rationale for Inclusion Criteria
1 – 3
In accordance with harmonized GCP
5 – 12
To select the adequate subject population with appropriate disease severity
4
For the safety of the study subjects
13 – 14
The impact of LCIG treatment 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.
Predominantly di-phasic dyskinesia, as per Investigator discretion.
2.
Patients who were treated with LCIG before.
3.
Patients who have had previous surgery for PD including, but not limited to deep 
brain stimulation (DBS) or cell transplantation.
4.
Participation in a concurrent interventional or observational study. 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
48
5.
Lack of motivation or insufficient language skills to complete the study 
questionnaires.
6.
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), atypical 
Parkinson Syndrome (e.g., Multiple System Atrophy, Progressive supranuclear 
Palsy, Diffuse Lewy Body disease) or other neurodegenerative disease that might 
mimic the symptoms of PD.
7.
Subject has any neurological deficit that might interfere with the study assessments 
(e.g., hemiparesis).
8.
Known hypersensitivity to levodopa, carbidopa or radiopaque material.
9.
Subject has contraindications to levodopa, (e.g., narrow angle glaucoma, malignant 
melanoma).
10.
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.
11.
Current diagnosis or history of drug or alcohol abuse (DSM-V-TR criteria) within 
12 months prior to screening visit.
12.
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).
13.
Currently experiencing or any known history of psychosis (e.g., troublesome 
hallucinations with or without insight) or delusions within 3 months prior to 
Screening.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
49
14.
A Mini-Mental State Examination (MMSE) score of < 24 at Visit 1 or significant 
cognitive impairment that, in the opinion of the Investigator, could impact the 
subject's ability to participate in the trial.
15.
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.
16.
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).
17.
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).
18.
Any malignant disease other than carcinoma in situ of the cervix or basal cell 
carcinoma of the skin within the past 5 years prior to Screening.  Subjects with 
prostate cancer or completely excised squamous cell carcinoma of the skin without 
reoccurrence within 2 years prior to Screening may be permitted to enroll 
following Investigator and AbbVie TA MD 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.
19.
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.
20.
Exposure to any investigational drug within 30 days prior to Screening.
21.
Previous enrollment in this study, any other LCIG study or any prior exposure to 
LCIG treatment.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
50
22.
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.
23.
Subject has significant current suicidal ideation within 1 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.
24.
A low B12 level or low-normal B12 level (less than 300 pg/mL or 221.4 pmol/L) 
with elevated methylmalonic acid (MMA), at Screening Visit 1.*
25.
Positive screen for drugs of abuse or medical marijuana, at Screening Visit 1.
26.
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.
27.
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.
28.
Consideration by the Investigator, for any reason, that the subject is an unsuitable 
candidate to receive LCIG treatment.
*
If treated and repeat labs confirm B12 levels rise above 300 pg/mL or 
221.4 pmol/L, subject is eligible to re-screen.
Rationale for Exclusion Criteria
1, 6, 7, 9, 15 – 18, 24, 25
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 treatment 
for safety events
5, 8, 10 – 14, 19, 22 – 23
To ensure safety of the subjects throughout the study
2 – 4, 20 – 21, 28
To exclude, or to minimize, the number of medications 
or other factors that could interfere with the LCIG 
treatment, or could add unnecessary variance or bias to 
safety evaluations


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
51
26 – 27
The impact of LCIG treatment on pregnancies and 
lactation is unknown
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving from 30 days prior to 
signing the Informed Consent Form, or receives during the study, must be recorded along 
with the reason for use, date(s) of administration including start and end dates, and dosage 
information including dose, route and frequency.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior Therapy (Prior to Randomization)
All medications taken by the subject during the study and 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.
Allowable Medications
Anti-Parkinsonian Medications
The following classes of anti-Parkinsonian medications will be allowed during the study:
Levodopa formulations
●
For the OMT group, all levodopa formulations are allowed
●
For the LCIG treatment group:


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
52
○
levodopa formulations can only be used at nighttime (the 8 hours when the 
pump is not in use) or as rescue medication
●
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
Dopamine agonists (not including apomorphine continuous infusion or PRN injection)
MAO-B inhibitors
Anti-cholinergics
Amantadine –
As an exception, subjects in both groups who take amantadine at the randomization 
visit (V3) must not discontinue this treatment and are required to continue this 
treatment for the entire study duration with the regimen kept stable unless the 
Investigator decides that it is medically indicated to discontinue this treatment.  If 
subjects do not take amantadine at the Visit 1 (Screening Visit 1), this treatment must 
not be initiated during the entire study duration.
General Requirements
Screening to Visit 3:  All anti-Parkinson's disease medications must be stable* for at least 
30 consecutive days prior to V3 baseline assessments.  
*A stable regimen is defined as no changes to the frequency of administration, dose of 
administration or total daily dose.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
53
Randomization to End of Treatment Period:
●
OMT Group:  all anti-PD medications should remain stable from 
randomization to the Week 12 visit and study assessments unless medically 
indicated.
●
LCIG treatment Group: Those subjects randomized to LCIG treatment must 
discontinue all other anti-PD medications other than amantadine 
(e.g., dopamine agonists, COMT-inhibitors, 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, over a 
period of up to 14 days.  With the exception of apomorphine, levodopa 
containing formulations or amantadine (see next paragraph), these medications 
may be restarted if indicated by the subject's individual condition, but not 
within the first 28 days after the PEG placement procedure.
As an exception, subjects in both groups who take amantadine at the randomization visit 
(V3) must not discontinue this treatment and are required to continue this treatment for 
the entire study duration with the regimen kept stable unless the Investigator decides that 
it is medically indicated to discontinue this treatment.  If subjects do not take amantadine 
at the Visit 1 (Screening Visit 1), this treatment must not be initiated during the entire 
study duration.
Anti-PD medications should only be adjusted if medically indicated
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 appropriate eCRF, except for 
study drug for subjects randomized to LCIG treatment.  All changes to concomitant 
medications, this includes all medications taken by subjects randomized to OMT, must be 
carefully documented on the Concomitant Medication eCRF.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
54
Medications for Management of Dyskinesia (OMT Treatment Group)
All medications used for the management of dyskinesia must be stable for at least 
30 consecutive days before the Randomization visit (V3).  These medications should then 
also remain stable for the duration of the study.
The Investigator can make modifications to these medications or additional medications if 
medically indicated after discussion with the AbbVie TA MD.
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.
Prohibited Medications (OMT and LCIG Treatment Groups)
The following medications (not comprehensive) are prohibited during the study.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
55
Table 3.
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 
treatment 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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
56
5.2.3.3
Rescue Therapy (LCIG Treatment 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 Treatment Group 
Only)
Those subjects randomized to the LCIG Treatment 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 treatment drug administration, levodopa-DOPA 
decarboxylase inhibitor (DDI) tablets or similar such as Levodopa + carbidopa = Sinemet, 
LD + CD + entacapone = Stalevo, Levodopa + Benserazide = Madopar 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.  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.
5.2.4
Contraception Recommendations and Pregnancy Testing
If female, subject must be either postmenopausal defined as:


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
57
●
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
●
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
●
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.
○
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.
○
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the women of child bearing potential (WOCBP) trial participant.
○
Intrauterine device (IUD).
○
Intrauterine hormone-releasing system (IUS).
○
Progestogen-only oral hormonal contraception, where inhibition of 
ovulation is not the primary mode of action, initiated at least 1 month prior 
to Study Day 1.
○
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).


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
58
If male subject must be surgically sterile (vasectomy with medical assessment confirming 
surgical success) or have a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), OR if sexually active 
with female partner(s) of childbearing potential must agree from Study Day 1 through 
4 weeks after the last dose of study drug to practice contraception with:
●
Condom use.
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  (Note:  Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).
●
Additionally, male subject agrees not to donate sperm from Study Day 1 
through 4 weeks after the last dose of study drug.
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 4
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.  For all 
study visits apart from V1 to V3 a ± 3 days visit window will be allowed.  All attempts 
should be made to return the subject to the planned visit schedule (e.g., if the subject is 
2 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 Treatment and the day 
after randomization for subjects randomized to OMT).


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
59
Table 4.
Study Activities
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 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
Xf
Concomitant Medication 
(including anti-PD and 
Dyskinesia medications)
X
X
X
X
X
X
X
X
X
X
X
Anti-PD Medication 
History
X
Physical Examinationg
X
X
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
X
Dermatological Examg
X
X
GI Examg
X
X
NJ or PEG-J decision 
X
Nasojejunal Tube 
Placement/Titrationh
(Optional)
X
PEG-J Placement 
Procedureh
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
60
Table 4.
Study Activities (Continued)
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 FUa
Transition to 
Commercial 
Visitsb
Radiological Check of 
Tube Placementi
X
PEG-J Site (Stoma) Check
Xj
X
X
Vital Signs/Weight
X
X
X
X
X
X
X
X
X
X
Height
X
ECG
X
X
X
Clinical Labs 
Xk
Xk
X
X
Urine Drug/Alcohol 
Screen
X
Special Laboratory Testsl
X
X
X
X
X
Pregnancy Testm
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
Dose Titration Diaryn
X
X
Subject Dosing Diary 
Completiono
X
X
X
X
X
PD Diary training and 
concordance evaluation
X
PD Diaryo
X
X
X
X
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
61
Table 4.
Study Activities (Continued)
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 FUa
Transition to 
Commercial 
Visitsb
LCIG System and Pump 
Training (Subject and 
Caregiver)
X
X
LCIG Titrationp
X
X
Study Drug Prescription 
Record (LCIG treatment 
group only)
X
X
X
X
X
X
X
Removal of PEG-Ja
X
LCIG Cassettes Dispensed
X
X
X
X
X
X
X
LCIG Cassettes Returned
X
X
X
X
X
X
MMSE 
X
Sleep Attacks 
Questionnaireq
X
X
X
X
X
X
X
X
C-SSRSr
X
X
X
X
X
X
X
X
X
X
MIDI 
X
X
X
X
X
X
X
X
X
UDysRSs
X
X
X
X
X
UPDRS II and IIIt
X
X
X
X
X
X
mAIMSu
X
X
X
X
X
PDQ-8
X
X
X
CGI-C 
X
X
X
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
62
Table 4.
Study Activities (Continued)
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 FUa
Transition to 
Commercial 
Visitsb
CGI-S
X
King's PD Pain Scale
X
X
X
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.
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 dyskinesia.
d.
Visit 4 for LCIG Treatment (LCIG) group only.
e.
Study-related assessments, procedures or activities cannot occur prior to subject completing signed informed consent process.  
f.
Update Medical/Neurological/PD History with any findings from Labs, Dermatologists, etc.
g.
At Screening Visit 1 and Randomization Visit 3 a full physical examination will be performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.  Prior to Visit 3, 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 3 and Week 12/ET visit.  If a suspicious lesion is present, a biopsyshould be 
obtained for proper diagnosis and confirmation that lesion does not meet exclusion criteria before the subject is randomized.
h.
For subjects randomized to LCIG treatment, a temporary NJ tube may be used to optimize the dose of LCIG before treatment witha 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, surgeon or interventional radiologist.  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.
i.
LCIG treatment 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.  Additional checks can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
j.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG-J.
k.
PT/PTT will be performed only at Screening Visit 1.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
63
Table 4.
Study Activities (Continued)
l.
Special labs to detect vitamin deficiencies, listed in Table 5, will be performed at the times indicated in Table 4.  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.
m.
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.
n.
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.
o.
The Subject Dosing Diary and the Parkinson's Disease Diary will be completed by the subjects or their caregivers for the 3 consecutive days prior to each visit.
p.
It is up to the discretion of the Investigator to determine how many titration days are necessary to obtain optimal clinical response.
q.
The Sleep Attacks Questionnaire will be used to screen for sleep attacks.  Results should be recorded in source but will not be entered in the clinical database.
r.
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.
s.
The subject's expected time of peak dose dyskinesia should be determined during screening and the UDysRS should be administered at this time throughout the study.
t.
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 Part III will only be done during Screening; all other UPDRS assessments will 
be done during "On" time.
u.
The mAIMS should be completed following the UDysRS at the subject's expected time of peak dose dyskinesia.
Note:
All applicable clinical, safety, health outcome and cognition assessments will be administered only by individuals qualified by the Sponsor.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
64
5.3.1.1
Study Procedures
The study procedures outlined in Table 4 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 multiple 
days.  
Informed Consent
Voluntary written informed consent must be obtained from each subject (and if 
appropriate, their caregiver) by the Investigator 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 4.  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.
Mini-Mental State Examination (MMSE)
The MMSE28 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 subject 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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
65
eligible for study participation.  Lower scores indicate greater impairment.  The MMSE 
will be administered at Visit 1 as indicated in Table 4.
Sleep Attacks Questionnaire
To prospectively monitor for possible development of sleep attacks, the subject will be 
evaluated for sleep attacks at the times indicated in Table 4.  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?
●
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 3 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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
66
Physical Examination
At Screening V1, V2 (optional visit) 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 including light touch and pinprick sensation, vibratory 
sensation, deep tendon reflexes, and strength assessments will be performed at the times 
indicated in Table 4.  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 that change in severity or frequency following randomization for the OMT 
group and the first dose of IP for the LCIG treatment group will be recorded as adverse 
events.
The Neurological Examination will assess:
●
Cranial nerves – assessment of cranial nerves II – XII, including fundoscopic 
examination
●
Motor system – assessment of tone, strength and abnormal movements
●
Sensory system – including light touch, pinprick, joint position and vibratory 
sense
●
Reflexes – assessment of deep tendon reflexes and plantar responses (Babinski 
sign)
●
Coordination – assessment of upper and lower extremities
●
Gait – assessment of base and tandem gait
The Neurological Examination performed at Visit 1, will serve as baseline for clinical 
assessment.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
67
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 V3 and at Week 12/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 Treatment 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, surgeon or interventional radiologist.  Total time to 
titration via NJ and PEG-J should not exceed 14 days.  Alternatively, subjects may 
proceed directly to placement of the PEG-J if deemed appropriate by the 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 Treatment 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 treatment 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. 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
68
PEG-Site (Stoma) Check (LCIG Treatment 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-giver 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 or interventional radiologist (preferably the 
physician who placed the PEG-J), or their designated qualified personnel within 24 hours 
and 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 4.  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.
Vital signs will include body weight will be measured at the times indicated in Table 4.  
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 4.  An 
attempt should be made to obtain all other ECGs at a consistent time of day.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
69
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.
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 5.  
The laboratory test results obtained at Visit 3 will serve as baseline for clinical assessment 
and are not intended to determine eligibility for randomization.  All clinical laboratory 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
70
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 only Screening Visit 1.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
71
Table 5.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Special Testsd
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 screeningd
Ethanol
U-etylglucuronide 
(U Etg)
U-etylsulphate 
(U-Ets)
Cannabinoids
Barbiturates
Benzodiazepines
Opiates
Methadone
Cocaine
Amphetamines
Thyroid Function Testse
Vitamin B12
f
Vitamin B6
f
Folic Acid
Methylmalonic 
Acid (MMA)f
Homocysteinef
a.
Only done at Visit 1.
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 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 labs at Visit 1 are exclusionary.
e.
Includes TSH and free T4 (Visit 1 only).
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 4.  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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
72
Urine Screens for Drugs of Abuse and Alcohol
A 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 in Table 5.  The 
urine drug screen analysis at Visit 1 will be performed by the certified central laboratory 
chosen for the study.
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 4.  
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 lab results 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
For all females of childbearing potential a serum pregnancy test will be performed at V1 
and Premature Discontinuation/End of Study.  A negative urine pregnancy test result is 
required to be done by the site prior to the NJ and/or PEG-J placement procedure and/or 
any radiological procedures.  Additional testing may be required per local regulations.
Minnesota Impulsive Disorders Interview (MIDI)
To monitor for development of intense impulsive behavior, the Minnesota Impulsive 
Disorders Interview (MIDI)29 will be administered at the times indicated in Table 4 or 
whenever relevant symptoms emerge.  If the subject's impulsivity during the Screening 
Period is judged to be clinically significant in the judgment of the Investigator, they will 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
73
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 
AbbVie TA MD should also be notified.  The MIDI will be administered as indicated in 
Table 4.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS)30 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 
AbbVie TA MD 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 AbbVie TA MD. 
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 "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.
The C-SSRS will be administered at the times outlined in Table 4.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
74
Unified Parkinson's Disease Rating Scale (UPDRS)
The Unified Parkinson's Disease Rating Scale (UPDRS)31 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
●
Part III – Motor Examination
●
Part IV – Complications of Therapy (including dyskinesias)
●
Part V – Modified Hoehn and Yahr Staging
Only Part II and Part III will be administered in this study.
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; all other UPDRS assessments will be done during "On" time.
The UPDRS will be obtained at the times indicated in Table 4.
Unified Dyskinesia Rating Scale UDysRS
The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to evaluate involuntary 
movements often associated with treated Parkinson's disease.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
75
The UDysRS is made up of the following sections:
●
Part 1 – Historical Disability (patient perceptions) of On-Dyskinesia impact
●
Part 2 – Historical Disability (patient perceptions) of Off-Dystonia impact
●
Part 3 – Objective Impairment (dyskinesia severity, anatomical distribution
over seven body regions and type (choreic or dystonic) based on four observed 
activities
●
Part 4 – Objective Disability based on Part 3 activities
The Historical Score is the sum of Parts 1 and 2 and the Objective Score is the sum of 
Parts 3 and 4.  The dimensions are evaluated through both an investigation and interview 
carried out by the physician/rater and self-administered questionnaire.  The UDysRS 
assessment will be performed by an experienced rater.  Rater training will be provided by 
the Sponsor as appropriate.  The subject's expected time of peak dose dyskinesia should 
be determined during screening and the UDysRS should be administered at this time 
throughout the study.
A Site Administrator will administer the UDysRS.  Subjects will be videotaped during the 
completion of the Part 3 activities.  The videotape will be transmitted to the Central 
Blinded Rater for scoring of Parts 3 and 4.  All subjects will be required to wear a pump 
during each videotape session to blind the assessor.  All subjects will wear a dummy 
pump at V3 and subjects randomized to OMT will wear a dummy pump at each treatment 
period assessment.  A detailed description of the process will be provided in the rater 
manual.
A mock UDysRS administration to allow subjects to familiarize themselves with the 
pump should be conducted before the actual study UDysRS assessment.
For the communication assessment the UDysRS administrator will comment on camera 
on the understandability of the speech using a standardized text.
The UDysRS will be obtained at the times indicated in Table 4.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
76
Modified Abnormal Involuntary Movement Scale (mAIMS)
The AIMS is a reliable and frequently used scale to assess tardive dyskinesia and thus has 
an emphasis on orofacial dyskinesia.32  For the purposes of dyskinesia assessment in PD, 
modifications of the original scale have been developed.  The mAIMS uses a uniform 
Likert type scoring system where each item is rated from 0 = none to 4 = severe.  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 mAIMS 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 assessments for mAIMS should be completed following the UDysRS at the subject's 
expected time of peak dose dyskinesia as per the times indicated in Table 4.
Parkinson's Disease Diary/PD Diaries 
The core of the Parkinson's Disease Diary (PD Diary) is the tool that the subject will use 
to record Parkinsonian symptoms.  The subject and/or caregiver will be prompted to 
answer the PD Diary whether the subject has been "ON," "OFF," or "ASLEEP" and what 
has been the severity of the dyskinesia (troublesome or not troublesome).  On PD Diary 
recording days, subjects will be instructed to make an entry upon waking and every 
30 minutes during their normal waking time.
Study site staff should make a call to the subjects in advance of their clinic visit to review 
with them the need to complete the PD Diary for the visit.
The PD Diary is to be recorded at the times indicated in Table 4.
Parkinson's Disease Diary Subject Training and Screening Requirements
During the Screening period, the subject and caregiver, if applicable, will be required to 
have Parkinson's Disease Diary training which will include how to understand their PD 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
77
symptomatology and how to complete the Parkinson's Disease Diary.  The "Parkinson's 
Disease Motor Diary Video Instruction" DVD may be used for this training.
Site personnel should emphasize the importance of completing the Parkinson's Disease 
Diary accurately.  It is to be completed for the full 24 hours of each day at half-hour time 
points in real-time during waking hours to ensure true evaluation of the subject's 
condition, reflecting both time awake and time asleep.  On the recording days (the 3 days 
prior to the visits indicated in Table 4), subjects will be instructed to make an entry every 
30 minutes during their waking time and upon awakening from time asleep.  The time the 
subject slept will also be indicated.  The subject should bring the completed Parkinson's 
Disease Diaries with them to the visits indicated in Table 4.
Following the initial Parkinson's Disease Diary training during Screening Visit 1, the 
subject will be given a Parkinson's Disease Diary to be filled in over a minimum period of 
3 hours for a concordance evaluation while they are in the clinic.  During this period, the 
subject must experience at least one transition from "Off" to "On" or from "On" to "Off," 
which must be observed by the Investigator.  The Investigator or an experienced and 
medically qualified study site designee (e.g., NP, PA, DO, MD, or PhD) assigned by the 
Investigator will also complete a separate Parkinson's Disease Diary for this period 
indicating their assessment of the subject's motor state.  There must be at least 75% 
concordance overall between the subject's Parkinson's Disease Diary and the Parkinson's 
Disease Diary completed by the Investigator or Investigator's qualified designee including 
concordance on at least 1 time interval of "Off," concordance on at least 1 time interval of 
"On" regardless of dyskinesia and at least 1 time interval of "On with dyskinesia" 
irrespective of whether the dyskinesia are troublesome or not troublesome.  The testing 
time can be extended in order to capture all required states.  If the concordance criteria are 
not met, the subject will undergo re-training of Parkinson's Disease Diary completion and 
repeat the concordance evaluation.  If the concordance criteria are not met again the 
subject should be considered not-eligible for the study.
After successful concordance evaluation, the subject will be instructed to complete 
3 consecutive days of Parkinson's Disease Diaries and return the completed diaries at 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
78
Randomization Visit 3.  The Parkinson's Disease Diary dispensed at Screening Visit 1 will 
be collected at the start of Randomization Visit 3, and will be reviewed prior to the 
conduct of any Visit 3 procedures.  The subject's compliance in entering Parkinson's 
Disease Diary data over the consecutive 3-day period should be evaluated.  Subjects must 
demonstrate a 75% or greater compliance rate of diary completion.  If the completion 
compliance rate is not met, the subject may be re-trained and the evaluation of compliance 
may be repeated.  An additional visit will be required.
The PD diary should be completed during the 72-hour period (3 days) prior to each clinic 
visit, as indicated in Table 4.  Subjects should be reminded with a phone call prior to each 
visit to complete the PD Diaries and to reinforce the importance of PD Diary completion.
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.  
Average score and 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 4.
Clinical Global Impression of Severity (CGI-S)
The Clinical Global Impression-Severity is a global assessment of current 
symptomatology and impact of illness on functioning.  The ratings are as follows:
1 = normal
2 = borderline ill
3 = mildly ill
4 = moderately ill
5 = markedly ill


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
79
6 = severely ill 
7 = among the most extremely ill 
A qualified rater will administer the CGI-S to the subject at the times indicated in Table 4.
King's PD Pain Scale
The King's PD Pain Scale is an easy to administer 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 
of this instrument have been recently evaluated.33  A qualified rater will administer the 
King's PD Pain Scale to the subject to assess for PD specific pain at the times indicated in 
Table 4.
Parkinson's Disease Questionnaire (PDQ-8)
The PDQ-834 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 4.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
80
Dose Titration Diary
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.
Study Drug Prescription Record (LCIG Treatment Group Only)
The subject's pump settings (morning dose volume in mL, continuous infusion rate in 
mL/hr, extra dose volume in mL and lock level) will be recorded on the Study Drug 
Prescription eCRF at the time of the first infusion of LCIG via NJ (if applicable), at the 
time of the first infusion of LCIG via PEG-J, and at the conclusion of each clinic visit in 
the study drug prescription record.
Subject Dosing Diary (LCIG Treatment 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 4.  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 treatment 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.
Subjects in the OMT group will record all anti-parkinsonian medications taken on the 
Subject Dosing Diary days in the diary.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
81
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.
Site Rater Training Requirements
The study scales/questionnaires will be administered only by individuals qualified by the 
Sponsor and the rater training vendor.  The UDysRS Parts 1 and 2 will be assessed and 
scored by site raters who are qualified based on MDS training.  Prior to administration, 
designated raters (Investigator or an experienced and qualified study site assigned by the 
Investigator) will be trained and where applicable certified in the use of the study 
scales/questionnaires.  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 rating scale and/or 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 where appropriate 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 study certification/training or 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
82
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 Central Rater Training Requirements
The objective portion of the UDysRS (Parts 3 and 4) will be assessed and scored by 
experienced blinded central raters who are qualified based on MDS training.
The blinded central raters will be blinded to the study protocol and the tested hypotheses 
and 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 a video recording of the interview with the subject.
The blinded central rater will score the UDysRS assessment at the times indicated in 
Table 4 with the baseline assessment occurring at Visit 3.
5.3.1.3
Ancillary Support
Sites will be appropriately trained and provided support on the initiation and titration of 
LCIG treatment prior to subject enrollment of the first subject at each site. 
Duodopa Nurse Specialist (DNS)/AbbVie Duodopa Specialist (ADS)/Nurse Educator 
(NE)
The Sponsor may provide ancillary support to the study sites by utilizing a Duodopa 
Nurse Specialist (DNS) to provide additional training to the Investigator and site 
personnel.  DNS services and training are methods of support in the implementation of the 
LCIG administration system at clinical sites.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
83
The functions of the DNS may include:
●
Provide ongoing education and support to the site personnel (Investigator, 
gastroenterologist or interventional radiologist, 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
5.3.3.1
Primary Efficacy Variable
The primary efficacy variable will be the change from baseline to Week 12 in UDysRS 
Total Score.
The UDysRS was chosen for the assessment of the primary endpoint because it was 
developed specifically for the assessment of dyskinesia in PD and is endorsed by the 
International Parkinson and Movement Disorder Society.24  Containing both self-
evaluation questions by the patient alone and physician-assessed items to objectively rate 
dyskinesia and off-dystonia, its clinimetric properties are excellent23 and it has been 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
84
demonstrated to be superior for detecting treatment effects compared to other available 
dyskinesia scales.24
5.3.3.2
Additional Efficacy and Health Outcome Variables
Secondary Endpoints (with hierarchical analysis)
●
ON time without troublesome dyskinesia as measured by the PD Diary
●
PDQ-8 Summary Index
●
CGI-C
●
UPDRS Part II Score
●
OFF time as measured by PD Diary 
●
UPDRS Part III Score
Additional Efficacy Endpoints are: 
●
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
●
ON time with troublesome dyskinesia and ON time without dyskinesia as 
measured by PD Diary 
●
mAIMS
Additional Health Outcome Endpoints: 
●
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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
85
●
Electrocardiogram
●
Vital signs and weight
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Minnesota Impulsive Disorders Interview (MIDI)
●
Sleep Attacks Questionnaire
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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
86
●
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 an End of Treatment/Week 12 
(V8) should be performed as soon as possible.
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 Treatment Group Only)
For subjects randomized to LCIG treatment, 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, surgeon 
or interventional radiologist.  Follow-up visit with examination should occur 1 week 
following the PEG-J removal.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
87
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.
5.5
Treatments
5.5.1
Treatments Administered
Subjects may be randomized to one of two treatment groups, OMT or LCIG treatment.
5.5.1.1
OMT
Those subjects randomized to OMT, will continue on their current anti-PD medication 
regimen for the duration of the study.  All anti-PD medications and medications to treat 
dyskinesia must remain stable for the duration of the study unless adjustments are 
medically indicated.  The Investigator will provide the prescription for continued OMT.
If modifications are needed, this should first be discussed with the AbbVie TA MD.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
88
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 
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
89
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. 35
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 
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.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
90
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.
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
91
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, interventional radiologist or experienced nurse if done via 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.
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, surgeon or 
interventional radiologist 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 interventional 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 interventional radiologist experienced with the placement of PEG-J tubes.  
Each study site should have one study designated gastroenterologist proceduralist, 
surgeon, or interventional radiologist and one backup who has experience with and a 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
92
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.
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 AbbVie 
TA MD.  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 
caregiver 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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
93
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, interventional radiologist, or their 
designated qualified personnel will examine the subject's stoma site between 2 to 7 days 
after PEG-J placement, and 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 6.
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 those alone.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
94
Table 7.
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
The Pump comes in a kit 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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
95
5.5.2.3
Storage and Disposition of Study Drugs
LCIG Storage
At the LCIG distribution depot, the cassettes with the LCIG suspension can be stored in 
the freezer (between –15°C/5°F and –25°C/–13°F) for up to 2 years.  After thawing, the 
LCIG suspension can be stored in a refrigerator (between 2°C/35.6°F and 8°C/46.4°F) for 
up to 12 weeks for US sites and up to a maximum of 15 weeks for OUS.  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.
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 to the study site (devices and 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 4-digit number by the 
IRT system.  At the end of 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 
treatment, the site will obtain the study drug kit numbers from IRT to dispense at the 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
96
designated Visits.  Study drug must not be dispensed without contacting the IRT.  Study 
drug may only be dispensed to subjects randomized to LCIG treatment in the study 
through the IRT.
This is an open-label study and all eligible subjects will receive OMT or LCIG treatment.
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.
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 receives extra or, if required, rescue doses.
5.5.5
Blinding
This is an open-label study with randomized treatment assignment.  All eligible subjects 
will be randomized in a 1:1 ratio through the IRT system to receive OMT or LCIG 
treatment in an open-label manner.  Site personnel will be blinded to the randomization 
schedule.
Central blinded raters will be used to rate Parts 3 and 4 of the UDysRS, the primary 
efficacy endpoint for this study.  Assessment obtained at V3 will serve as the baseline for 
clinical assessment.  The scales will also be performed at Weeks 2, 4, 8, and 12.  The 
scoring for Parts 3 and 4 are to be performed by a trained central blinded 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 on the video recording of the subject.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
97
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.
Treatment regimen compliance will be also be assessed by the Subject Dosing Diary.
LCIG therapeutic systems are to be received intact and in the correct amounts.  This will 
be documented by the Investigator or designee 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 destructed by the depot.
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
98
LCIG) will be returned to the depot, according to instructions from AbbVie and according 
to local regulations.  Labels must remain attached to the containers.
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.
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 treatment 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 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
6.
The majority of subjects 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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
99
5.6.2
Appropriateness of Measurements
The Unified Dyskinesia Rating Scale (UDysRS) is a tool used to evaluate involuntary 
movements often associated with treated Parkinson's disease.
The Unified Dyskinesia Rating Scale (UDysRS) is a comprehensive rating tool that 
captures patient perceptions, time factor of dyskinesia, anatomical distribution, 
phenomenology (dystonia versus other dyskinesias), objective impairment, severity and 
disability of dyskinesia and dystonia in PD.  The UDysRS was developed specifically to 
assess dyskinesia in PD and has been applied to PD populations.  Although relatively 
new, multiple clinical trials of new putative anti-dyskinesia agents are currently using 
UDysRS as the primary endpoint.  The UDysRS contains both self-evaluation questions 
(by the patient alone or with their caregivers) and items that are assessed directly by the 
physician to objectively rate the abnormal movements associate with PD.  The UDysRS 
contains two primary sections (historical and objective) and each section is divided into 
two parts.  All parts consist of several items and each item is scored on a scale from 0 – 4 
in a Likert model (0 = normal to 4 = severe) and the total score can range from 0 – 104.  
Table 8 lists the sections and corresponding parts of the UDysRS.
Table 8.
UDysRS Sections
Section
Part
Completed by
Measure
Number 
of Items
Score 
Range
Historical 
disability
Part 1
Patient/Caregiver
Patient perception of on-dyskinesia 
impact
11 items
0 – 44
Part 2
Patient/Caregiver
Patient perception of off-dystonia 
impact
4 items
0 – 16
Objective
Part 3
HCP
Rating of dyskinesia based on HCP 
observation of patients performing 
4 motor tasks (communication, 
drinking, dressing ambulation)
7 items
0 – 28
Part 4
HCP
Disability scale rating based on 
HCP's observation of activities 
performed by patient in Part 3
4 items
0 – 16


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
100
UDysRS Validation and Psychometric Properties
The original development and validation study was conducted by Goetz et al (2008).  
Twenty international movement disorder experts participated in the study.  Internal 
consistency, factor structure and reproducibility of the scale were determined in 70 PD 
patients.  The UDysRS showed high internal consistency for both the subjective 
(Cronbach's alpha = 0.92) and objective rating sections (Cronbach's alpha = 0.97).  Inter-
rater reliability for impairment and disability ranged from fair (kappa 0.4 – 0.59) to very 
good (kappa ≥ 0.8).  The inter-rater reliability for the total score was very good (kappa 
0.89).  Intra-rater reliability also ranged from fair (kappa 0.4 – 0.59) to very good (kappa 
> 0.8) for both impairment and disability.  The intra-rater reliability for the total score was 
also very good (kappa 0.90).  Repeated measures ANOVA used to assess ability to detect
change in UDysRS Parts 3 and 4; the UDysRS demonstrated an effect size = 0.138, with 
sensitivity to detect a treatment difference as small as 80% of a standard deviation 
(Goetz 2013).24  Evidence is supportive of the ability of Parts 3 and 4 to detect change, 
however Parts 1 and 2 were not assessed.  Convergent and discriminant validity have also 
not been assessed.
The UDysRS is a comprehensive rating tool to measure dyskinesia and has been studied 
clinimetrically as both a consistent and reliable measure.  The scale however has not been 
assessed for construct and content validity.
Additional analysis will be performed to provide evidence on the construct validity of the 
UDysRS.  Convergent validity will be evaluated by Spearman rank correlations between 
UDysRS total score (and sub-scores) and the AIMS score and Parkinson's Disease Diary 
assessment of severity of dyskinesia.  In addition, the association with indirectly related 
constructs to dyskinesia, the PDQ-8 total score (measuring the PD-specific health status 
and quality of life) as well as the UPDRS scores for Parts II – III will be determined.  
Correlations ≥ 0.30 are hypothesized to support convergent validity.  Discriminative 
validity will be explored by sub-group analyses.  The UDysRS total score will be 
stratified by the Hoehn and Yahr stages and tested using the Kruskal-Wallis test.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
101
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.36
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 treatment, 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 12 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: 
●
An active pharmacological agent 
●
Device component(s) (cassette, tubing, pump, connectors, etc.).


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
102
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.8.2).  For adverse events, please refer to Sections 6.1
through 6.6.  For product complaints, please refer to Section 6.8.
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.
6.2
Definitions
6.2.1
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.
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
103
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.
6.2.2
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, 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.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
104
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.
6.2.3
Adverse Events of Special Interest
Adverse events of special interest (AESI) are:
●
Gastrointestinal and gastrointestinal procedure related events
●
Polyneuropathy


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
105
●
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 will be issued within the Electronic Data Capture (EDC) system once 
applicable.  The Investigator will 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 6.6.
6.3
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
106
6.4
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
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
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.
6.5
Adverse Event Collection Period
Protocol-related non-serious 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 and removal of the PEG-J tube or last 
LCIG Commercial Transition Visit have elapsed will be collected, whether solicited or 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
107
spontaneously reported by the subject.  In addition, 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.
Figure 3.
Adverse Event Collection
6.6
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) 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 the site being made aware of the serious adverse 
event.
Email:  
FAX to:  




Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
109
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. 
6.7
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.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
6.8
Product Complaint
6.8.1
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 components.
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
110
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.
6.8.2
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 the 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
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal Investigator is responsible for notifying 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
111
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitors:
Primary Contact:
Avenida de Burgos, 91
28050 MADRID
SPAIN
Email:
Office:
Mobile:
Fax:
Alternate Contact:
1 North Waukegan Road
North Chicago, IL 60064
USA
Email:
Office:
Mobile
Fax:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation.  Protocol deviations affecting subject safety or data robustness should be 
reported in EU Member States where applicable.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
8.1.1
Analysis Datasets
Efficacy Dataset
Unless specified otherwise, the efficacy analyses will be performed on the intent-to-treat 
(ITT) dataset which will include all subjects who are randomized to the optimized medical 
treatment (OMT), and all subjects who are randomized to LCIG treatment and received at 
least one dose of study drug following PEG-J placement.  For assessments of efficacy, the 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
112
treatment period will begin the day after randomization 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.
Safety Dataset
The safety analyses will be performed on the safety dataset which will include all subjects 
who are randomized to OMT and all subjects who are randomized to LCIG treatment and 
have a study tube (NJ or PEG-J) placement procedure.  For assessments of safety, the 
treatment period will begin the day after randomization for subjects randomized to OMT, 
and the day of initial study tube placement (NJ or PEG-J) for subjects randomized to 
LCIG treatment.  The treatment period will end on the day of the final visit for subjects 
randomized to OMT.  For subjects randomized to LCIG treatment, the treatment period 
will end on the day of final study tube removal if all study tubes are removed on or after 
the last day of LCIG study drug infusion.  For all other subjects randomized to LCIG 
treatment, the treatment period will end on the day of the final visit.  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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
113
deviation, median, minimum, and maximum) will be provided for each treatment group, 
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.
Baseline UDysRS total score will be summarized for the ITT dataset.  One-way analysis 
of variance (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 be 
summarized for the ITT dataset.
Subject Disposition
The number and percentage of subjects contributed by each country and site will be 
summarized for each treatment group and for both treatment groups combined for the 
safety dataset.
The number and percentage of subjects who prematurely discontinue study drug will be 
summarized by treatment group and overall for the safety data set 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 drug, 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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
114
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
Unless otherwise specified, all efficacy analyses will be performed on the ITT dataset and 
comparisons between the OMT and LCIG treatment groups will be performed with two-
sided tests at the significance level of 0.050.
8.1.3.1
Primary Efficacy Analysis
The primary efficacy variable is the mean change from baseline to Week 12 for the 
UDysRS total score.
UDysRS Total Score
The UDysRS was developed to evaluate dyskinesia in Parkinson's disease.  It contains 
two primary sections with 26 questions:
Historical [Part 1 (On-Dyskinesia) and Part 2 (Off-Dystonia)]
Objective [Part 3 (Impairment) and Part 4 (Disability)]
Part 1 contains 11 questions about the on time dyskinesia and the impact of on-dyskinesia 
on experiences of daily living.  Part 2 contains 4 questions of off-dystonia rating.  Part 3 
contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 
contains 4 questions regarding dyskinesia disability.  Each question is scored with respect 
to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3= moderate 
and 4 = severe.  The UDysRS total score is obtained by summing the item scores, ranging 
from 0 to 104.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
115
Primary Analysis Model
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 OMT treatment at the Week 12 Visit.
Additional Analysis of the Primary Efficacy Variable
Analysis of covariance (ANCOVA) analyses will be carried out on change from baseline 
to final UDysRS total score.  The ANCOVA model will contain treatment and country as 
the main effects and baseline score as the covariate.
The ITT dataset will not include subjects randomized to LCIG who prematurely 
discontinue before receiving their first LCIG infusion.  To evaluate the impact of not 
including these subjects in the primary efficacy analysis, a sensitivity analyses will be 
carried out 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 a post-randomization assessment of UDysRS.
8.1.3.2
Secondary Efficacy Analysis
The secondary efficacy variables are the mean change from baseline to Week 12 in the 
following measures:
●
"ON" time without troublesome dyskinesia as measured by the PD Diary
●
Parkinson's Disease Questionaire-8 (PDQ-8) summary index
●
Clinical Global Impression of Change (CGI-C) Score
●
UPDRS Part II Score
●
"OFF" time as measured by the PD Diary
●
UPDRS Part III Score


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
116
Each secondary efficacy variable will be analyzed with the same MMRM model as the 
primary analysis.  PD Diary variables will be normalized to a 16 hour awake time and the 
time recorded by the subject on the 3 diaries completed prior to each visit will be 
averaged.
If the primary efficacy variable is statistically significant, each of the secondary variables 
will be tested using the fixed sequence above as a gatekeeping procedure and at α level of 
0.050.  Testing will cease at the point that a secondary variable fails to demonstrate 
statistical significance. 
8.1.3.3
Additional Efficacy and Health Outcomes Analyses
Efficacy will also be assessed using the following additional measures:
●
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
●
"ON" time with troublesome dyskinesia and "ON" time without dyskinesia as 
measured by the PD Diary
●
mAIMS
Health outcomes will also be assessed using the following additional measures:
●
King's PD Pain Scale
●
Percentage (%) of CGI-C responders (response of "minimally improved," 
"much improved" or "very much improved")
Continuous endpoints will be analyzed with the same MMRM model as the primary 
analysis.  Categorical endpoints will be analyzed with a Fisher's exact test.
Missing data are expected to occur at random and to be largely due to co-morbidities in 
this advanced Parkinson's disease population.  To evaluate this assumption, the MMRM 
analysis of the primary and secondary variables will be repeated using only subjects who 
completed the planned treatment period and additional sensitivity analyses to evaluate the 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
117
impact of missing data on the primary efficacy results will be performed.  These 
sensitivity analyses will be described in the Statistical Analysis Plan (SAP).
8.1.4
Safety Analysis
All safety analysis will be performed on the safety dataset unless otherwise specified.  
Comparisons between LCIG treatment 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 Fisher's exact test.
8.1.4.1
OMT and LCIG Treatment 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 LCIG device exposure will 
be calculated for each subject as the date of the last study tube exposure minus the date of 
the first study tube placement procedure plus 1.  For subjects with all study tubes removed 
on or after the last day of LCIG study drug infusion, the date of last study tube exposure 
will be the last tube removal date.  For all other subjects randomized to LCIG treatment, 
the date of last study tube exposure will be the day of the final visit.  The duration of 
OMT and LCIG study drug exposure and LCIG device exposure will be summarized with 
descriptive statistics (number of subjects with non-missing data, mean, and standard 
deviation, median, minimum and maximum).
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
118
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 an 
SAP prior to database lock.
A treatment-emergent adverse event (TEAE) is defined as any adverse event with onset 
during the treatment period or within 30 days of the end of the treatment period:
●
For the OMT group this includes all adverse events with onset after the day of 
randomization and within 30 days following the last visit.
●
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.  For all other LCIG treatment subjects, 
this will include all adverse events with onset on or after the date of the initial 
study tube placement procedure and no more than 30 days following the last 
visit.
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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
119
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 treatment group, as well as adverse 
events during the transition period for LCIG treatment 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 and for both treatment groups combined.  For this analysis, 
the average of multiple observations on the same day will be calculated and treated as the 
observation for the day.
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 for 
each treatment group.
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 for each treatment group and for both treatment groups combined.
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 and for 
both treatment groups combined.  For this analysis, the average of multiple observations 
on the same day will be calculated and treated as the observation for the day. 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
120
Criteria for potentially clinically significant (PCS) values for selected vital sign and 
weight variables will be pre-specified 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.
8.1.4.5
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 and for both treatment groups 
combined.  For this analysis, the average of multiple observations on the same day will be 
calculated and treated as the observation for the day. 
Criteria for potentially clinically significant (PCS) values for selected ECG variables will 
be pre-specified 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 for 
each treatment group and for both treatment groups combined.
8.1.4.6
Additional Safety Variables
The following additional summaries of safety measures will be prepared.
●
The number of subjects with 1 or more positive screens on a Minnesota 
Impulsive Disorders Interview (MIDI) module at baseline as well as during the 
treatment period, and
●
The number of subjects with 1 or more affirmative responses to the Columbia 
Suicide Severity Rating Scale (C-SSRS) at baseline as well as during the 
treatment period.
8.1.5
Interim Analysis
No interim analysis is planned for this study.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
121
8.2
Determination of Sample Size
Approximately 60 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either optimized medical treatment (OMT) or LCIG treatment.  Subject randomization 
will be stratified by country.  For sample size determination, it is assumed that the 
difference of improvement is 10 points on UDysRS total score between the LCIG 
treatment group and OMT group based on results reported by Pahwa et al. 37  The pooled 
standard deviation is assumed to be 12 based on results reported by Goetz et al. 24  
Assuming that the treatment group difference is 10 points and the pooled standard 
deviation is 12, 27 subjects per group will have 85% power to declare statistical 
significance on the primary endpoint at a two-sided significance level of 0.050.  It is 
further assumed that 10% of randomized subjects in either treatment group will not 
provide post-randomization efficacy assessment.  Therefore the total planned enrollment 
is decided to be approximately 60 subjects.
8.3
Randomization Methods
Approximately 60 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either LCIG or OMT at the end of Visit 3.  Subject randomization will be stratified by 
country.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
122
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.
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.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject.  The subject must be able to understand the nature of the study and have the 
opportunity to have any questions answered by the Investigator.  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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
123
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 Investigator will prepare the 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 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 
Investigator will revise the consent form and explanatory material based on the 
information without delay and will obtain the approval of the IRB 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 
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
124
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(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.
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 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
125
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.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
126
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.
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 retain any records related to the study according to local 
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
127
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 12 Week Study Comparing Efficacy of 
Levodopa-Carbidopa Intestinal Gel/Carbidopa-Levodopa Enteral 
Suspension and Optimized Medical Treatment on Dyskinesia in 
Subjects with Advanced Parkinson's Disease
DYSCOVER (DYSkinesia COmparative interventional trial on 
Duodopa VERsus oral medication)
Protocol Date:
26 May 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
128
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/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
129
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.
Olanow CW, Kieburtz K, Odin P, et al.  Continuous intrajejunal infusion of 
levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease:  a 
randomised, controlled, double-blind, double-dummy study.  Lancet Neurol.  
2014;13(2):141-9.
17.
Slevin JT, Fernandez HH, Zadikoff C, et al.  Long-term safety and maintenance of 
efficacy of levodopa-carbidopa intestinal gel:  an open-label extension of the 
double-blind pivotal study in advanced Parkinson's disease patients.  J Parkinsons 
Dis.  2015;5(1):165-74.
18.
Fernandez HH, Standaert DG, Hauser RA, et al.  Levodopa-carbidopa intestinal gel 
in advanced Parkinson's disease:  final 12-month, open-label results.  Mov Disord.  
2015;30(4):500-9.
19.
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.
20.
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
130
21.
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.
22.
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.
23.
Goetz CG, Nutt JG, Stebbins GT, et al.  T The Unified Dyskinesia Rating Scale: 
presentation and clinimetric profile.  Mov Disord.  2008;23(16):2398-403.
24.
Goetz CG, Stebbins GT, Chung KA, et al.  Which dyskinesia scale best detects 
treatment response?  Mov Disord.  2013;28(3):341-6.
25.
Antonini A, Fung VS, Boyd JT, et al.  Effect of levodopa-carbidopa intestinal gel 
on dyskinesia in advanced Parkinson's disease patients.  Mov Disord.  
2016;31(4):530-7.
26.
Poewe et al.  Global Long-term Registry on Efficacy and Safety of Levodopa-
Carbidopa Intestinal Gel in Patients with Advanced Parkinson's Disease in Routine 
Care (GLORIA) – Interim Results in a Subgroup of Patients with Dyskinesia at 
Baseline.  2015.
27.
AbbVie.  Levodopa-Carbidopa Investigator's Brochure Edition 11.  06 April 2016.
28.
Folstein SE, Folstein SE, McHugh PR.  "Mini-mental state."  A practical method 
for grading the cognitive state of patients for the clinician.  J Psychiatry Res.  
1975;12(3):189-98.
29.
Christenson GA, Faber JR, de Zwann M.  Compulsive buying:  descriptive 
characteristics and psychiatric comorbidity.  J Clin Psychiatry.  1994;55(1):5-11.
30.
Columbia-Suicide Severity Rating Scale (C-SSRS) [homepage on the Internet].  
Columbia University Medical Center.  Available from:  
http//www.cssrs.columbia.edu/.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
131
31.
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.
32.
Guy W.  ECDEU Assessment Manual for Psychopharmacology:  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, Rockville, Md, USA.; 1976;534-7.
33.
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.
34.
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.
35.
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.
36.
Duodopa Intestinal Gel [Summary of Product Characteristics].  North Chicago, IL; 
AbbVie Inc., 2014.
37.
Pahwa R, Tanner CM, Hauser RA, et al.  Amantadine extended release for 
levodopa-induced dyskinesia in Parkinson's disease (EASED Study).  Mov Disord.  
2015;30(6):788-95.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
132
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
133
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
134
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Global Medical Affairs
Global Medical Affairs
Clinical
Clinical
Clinical
Clinical
Statistics
Statistics


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
135
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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
136
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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
137
Appendix D.
Potentially Clinically Significant Laboratory Values for Study M15-535
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
--
Hemaglobin 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
Hemaglobin 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
--


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
138
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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
139
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
Hypermagnesemia
3
> 3.0 mg/dL
> ULN – 3.0 mg/dL
--
> 3.0 – 8.0 mg/dL
> 8.0 mg/dL
> 1.23 mmol/L
> ULN – 1.23 mmol/L
> 1.23 – 3.30 mmol/L
> 3.30 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


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
140
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
Hypomagnesemia
3
< 0.9 mg/dL
< LLN – 1.2 mg/dL
< 1.2 – 0.9 mg/dL
< 0.9 – 0.7 mg/dL
< 0.7 mg/dL
< 0.4 mmol/L
< LLN – 0.5 mmol/L
< 0.5 – 0.4 mmol/L
< 0.4 – 0.3 mmol/L
< 0.3 mmol/L; 
life-threatening 
consequences
Hyponatremia
3
< 130 mmol/L
< LLN – 130 mmol/L
--
< 130 – 120 mmol/L
< 120 mmol/L; 
life-threatening 
consequences


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
141
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).


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
142
Appendix E.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Global Protocol Change
Change the study duration from 26 weeks to 12 weeks.
Specific Protocol Changes
Section 1.1  Synopsis
"Name of Study Drug:" previously read:
Levodopa-Carbidopa Intestinal Gel (OUS)/Carbidopa-Levodopa Enteral Suspension (US)
Has been changed to read:
Levodopa-Carbidopa Intestinal Gel (Outside United States)/Carbidopa-Levodopa Enteral 
Suspension (United States)
Section 1.1  Synopsis
Subsection Objectives:
Heading "Health Related Outcomes Will Be Measured by:"
Add:  new fourth bullet
Clinical Global Impression of  Severity (CGI-S)


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
143
Section 1.1  Synopsis
Subsection Methodology:
Figure 1:  Study Design Schematic previously read:
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any reason.  
7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
144
Has been changed to read:
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any reason.  
7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.
Section 1.1  Synopsis
Subsection Methodology:
Heading "Treatment Period V4 – V8"
First paragraph, first sentence previously read:
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).
Has been changed to read:
Those subjects randomized to continue OMT will remain on their current optimized 
regimen and will have study visits at the end of Weeks 2, 4, 8, and 12 following 
randomization (V3). 


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
145
Section 1.1  Synopsis
Subsection Methodology:
Heading "Treatment Period V4 – V8"
Second paragraph, second sentence previously read:
Those subjects randomized to LCIG treatment must discontinue all other anti-PD 
medications (e.g., dopamine agonists, COMT-inhibitors, MAO-B inhibitors, anti-
cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG treatment initiation on 
Day 1 (V4); these medications should be tapered off according to their individual package 
insert, and at the discretion of the Investigator, over a period of up to 14 days.
Has been changed to read:
Those subjects randomized to LCIG treatment must discontinue all other anti-PD 
medications except amantadine (e.g., dopamine agonists, COMT-inhibitors, MAO-B 
inhibitors, anti-cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG treatment 
initiation on Day 1 (V4); these medications should be tapered off according to their 
individual package insert, and at the discretion of the Investigator, over a period of up to 
14 days.
Section 1.1  Synopsis
Subsection Methodology:
Heading "Treatment Period V4 – V8"
Fourth paragraph, last sentence previously read:
Subjects on LCIG treatment will return for study visits at the end of Weeks 2, 6, 12 and 
26 and following PEG-J placement.
Has been changed to read:
Subjects on LCIG treatment will return for study visits at the end of Weeks 2, 4, 8, and 12 
and following PEG-J placement.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
146
Section 1.1  Synopsis
Subsection Methodology:
Heading "Treatment Period V4 – V8"
Delete:  fifth paragraph
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.
Section 1.1  Synopsis
Subsection Methodology:
Heading "Study Follow-Up"
Last paragraph previously read:
For all study treatment visits (V4 to V9) a ± 3 days visit window will be allowed.  The 
drug dispensing visits will occur at Weeks 17 and 22 with an allowed visit window of 
± 7 days if deemed necessary
Has been changed to read:
For all study visits apart from V1 to V3 a ± 3 days visit window will be allowed.
Section 1.1  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Exclusion:"
Delete:  Criterion 4
Patients with previous treatment with continuous subcutaneous apomorphine infusion.
Section 1.1  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
Subheading "Additional Efficacy Endpoints are:" 
Add:  new first bullet
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
147
Section 1.1  Synopsis
Subsection Criteria for Evaluation:
Heading "Efficacy:"
Subheading "Additional Health Outcome Endpoints are:"
Delete:  last bullet
Percentage (%) of CGI-C responders ("minimally improved," "much improved" or "very 
much improved")
Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Subheading "Additional Efficacy and Health Outcome Analyses"
First paragraph
Add:  new first bullet
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Subheading "Additional Efficacy and Health Outcome Analyses"
Second paragraph
Delete:  last bullet
Percentage (%) of CGI-C responders ("minimally improved," "much improved" or "very 
much improved")
Section 1.1  Synopsis
Subsection Statistical Methods:
Heading "Efficacy:"
Subheading "Additional Efficacy and Health Outcome Analyses"
Last paragraph
Delete:  last sentence
Categorical endpoints will be analyzed with a Fisher's exact test.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
148
Section 1.2  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "OUS"
OUS
Outside United States
Section 3.0  Introduction
Subsection UDysRS Validation and Psychometric Properties
First paragraph, last sentence previously read:
Convergent, content and discriminant validity have also not been assessed.
Has been changed to read:
Convergent and discriminant validity have also not been assessed.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
149
Figure 2.  Study Design Schematic
Previously read:
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any reason.  
7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
150
Has been changed to read:
*
Follow up period only applicable to LCIG treatment arm subjects that have discontinued the study for any reason.  
7 days after the PEG-J removal, a follow-up visit (V9) will be conducted.
Section 4.0  Study Objective
Subsection Health Related Outcomes Will Be Measured by:
Add:  new fourth bullet
Clinical Global Impression of Severity (CGI-S)
Section 5.1.1  Screening Period
Subsection Visit 1 (V1)
Fourth bullet
Add:  new last sentence
If the concordance criteria are not met again the subject should be considered not-eligible 
for the study.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
151
Section 5.1.1  Screening Period
Subsection Visit 3 (V3)
First paragraph
Add:  new last sentence
The UDysRS shall be administered and the videotape forwarded to the Central Blinded 
Rater on the first day of assessments.
Section 5.1.2  The Treatment Period
Previously read:
For all study treatment visits (V4 to V9) a ± 3 days visit window will be allowed.  The 
drug dispensing visits will occur at Weeks 17 and 22 with an allowed visit window of 
± 7 days if deemed necessary.
Has been changed to read:
For all study visits apart from V1 to V3 a ± 3 days visit window will be allowed.  
Section 5.1.2.2  LCIG Treatment Group
Subsection Tapering of Anti-PD Medications Other Than Levodopa
First paragraph, first sentence previously read:
Subjects randomized to LCIG treatment must discontinue all other anti-PD medications 
(e.g., dopamine agonists, COMT-inhibitors, MAO-B inhibitors, anti-cholinergics, and 
subcutaneous apomorphine, etc.) prior to LCIG treatment initiation on Day 1 (V4); these 
medications should be tapered off within 14 days after randomization according to the 
discretion of the Investigator.  
Has been changed to read:
Subjects randomized to LCIG treatment must discontinue all other anti-PD medications 
other than amantadine (e.g., dopamine agonists, COMT-inhibitors, MAO-B inhibitors, 
anti-cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG treatment initiation 
on Day 1 (V4); these medications should be tapered off within 14 days after 
randomization according to the discretion of the Investigator.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
152
Section 5.1.2.2  LCIG Treatment Group
Subsection LCIG Initiation and Titration
First paragraph, second sentence previously read:
All other oral anti-PD medications must be stopped prior to LCIG initiation.
Has been changed to read:
All other oral anti-PD medications other than amantadine must be stopped prior to LCIG 
initiation.
Section 5.1.2.2  LCIG Treatment Group
Subsection LCIG Initiation and Titration
Fourth paragraph
Delete:  eighth and ninth sentence
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.
Section 5.1.2.2  LCIG Treatment Group
Subsection Treatment:  Visit 5 (Week 2) Initial Post-PEG-J Evaluation Through 
Visit 8 (Week 26)
First paragraph, first sentence previously read:
Visit 5 will be conducted at Week 2, 14 days post PEG-J insertion.
Has been changed to read:
Visit 5 will be conducted at Week 2, 14 days post NJ and/or PEG-J insertion.
Section 5.1.2.2  LCIG Treatment Group
Subsection Treatment:  Visit 5 (Week 2) Initial Post-PEG-J Evaluation Through 
Visit 8 (Week 26)
First paragraph, fifth sentence previously read:
Visits 6, 7 and 8 at the end of Weeks 6, 12 and 26 respectively will be recorded on the 
appropriate eCRF and the assessments completed as in Table 4.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
153
Has been changed to read:
Visits 6, 7 and 8 at the end of Weeks 4, 8 and 12 respectively will be recorded on the 
appropriate eCRF and the assessments completed as in Table 4.
Section 5.1.2.2  LCIG Treatment Group
Subsection Treatment:  Visit 5 (Week 2) Initial Post-PEG-J Evaluation Through 
Visit 8 (Week 26)
Heading "Drug Dispensing Visits"
Delete:  heading title and text
Drug Dispensing Visits
The drug dispensing will occur during each of the study visit from V4 (Day1) until V8 
(Week 26).  In addition, LCIG 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.  
Section 5.1.3  Study Follow-Up 
Subsection Commercial Transition Visits (LCIG Treatment Subjects Continuing on 
Commercial Product)
Last paragraph, last sentence previously read:
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 
Adverse Drug Reaction (ADR) reporting in accordance with local instructions.
Has been changed to read:
Follow-up care in these circumstances will be based on the judgment of the subject's 
personal physician and, following the 30 day SAE/AE follow-up period, no formal 
collection of data will be conducted except for regular Adverse Drug Reaction (ADR) 
reporting in accordance with local instructions.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
154
Section 5.2.2  Exclusion Criteria
Delete:  Criterion 4
Patients with previous treatment with continuous subcutaneous apomorphine infusion.
Section 5.2.2  Exclusion Criteria
Subsection Rationale for Exclusion Criteria
Previously read:
1, 7, 8, 10, 16 – 19, 25, 26
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 treatment 
for safety events
6, 9, 11 – 15, 20, 23 – 24
To ensure safety of the subjects throughout the study
2 – 5, 21 – 22, 29
To exclude, or to minimize, the number of medications 
or other factors that could interfere with the LCIG 
treatment, or could add unnecessary variance or bias to 
safety evaluations
27 – 28
The impact of LCIG treatment on pregnancies and 
lactation is unknown
Has been changed to read:
1, 6, 7, 9, 15 – 18, 24, 25
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 treatment 
for safety events
5, 8, 10 – 14, 19, 22 – 23
To ensure safety of the subjects throughout the study
2 – 4, 20 – 21, 28
To exclude, or to minimize, the number of medications 
or other factors that could interfere with the LCIG 
treatment, or could add unnecessary variance or bias to 
safety evaluations
26 – 27
The impact of LCIG treatment on pregnancies and 
lactation is unknown


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
155
Section 5.2.3.2  Concomitant Therapy
Subsection General Requirements
Heading "Randomization to End of Treatment Period:"
Last bullet, first sentence previously read:
LCIG treatment Group:  Those subjects randomized to LCIG treatment must 
discontinue all other anti-PD medications (e.g., dopamine agonists, COMT-inhibitors, 
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, over a period of up to 
14 days.
Has been changed to read:
LCIG treatment Group:  Those subjects randomized to LCIG treatment must 
discontinue all other anti-PD medications other than amantadine (e.g., dopamine agonists, 
COMT-inhibitors, 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, over 
a period of up to 14 days.
Section 5.2.3.2  Concomitant Therapy
Subsection General Requirements
Heading "Randomization to End of Treatment Period:"
Last paragraph, first sentence previously read:
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 treatment.  
Has been changed to read:
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 appropriate eCRF, except for 
study drug for subjects randomized to LCIG treatment.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
156
Section 5.3.1  Efficacy and Safety Measurements Assessed and Flow Chart
Third and fourth sentence previously read:
For all study treatment visits (V4 to V9) a ± 3 days visit window will be allowed.  The 
drug dispensing visits will occur at Weeks 17 and 22 with an allowed visit window of 
± 7 days if deemed necessary.
Has been changed to read:
For all study visits apart from V1 to V3 a ± 3 days visit window will be allowed.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
157
Table 4.  Study Activities
Header row previously read:
OMT/LCIG
LCIG Treatment
OMT/LCIG 
Treatment
LCIG 
Treatment 
(Drug 
Dispensing 
Visits Only)
OMT/ 
LCIG 
Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
6
V7 
Wk 
12
Wk 
17
Wk 
22
V8 
Wk 26/ET
V9 
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Has been changed to read:
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9 
Wk 
13 
FUa
Transition to 
Commercial 
Visitsb


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
158
Table 4.  Study Activities
Activity "Concomitant Medication (including anti-PD and Dyskinesia medications)" previously read:
OMT/LCIG
LCIG Treatment
OMT/LCIG 
Treatment
LCIG 
Treatment 
(Drug 
Dispensing 
Visits Only)
OMT/ 
LCIG 
Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
6
V7 
Wk 
12
Wk 
17
Wk 
22
V8 
Wk 26/ET
V9 
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Concomitant Medication 
(including anti-PD and 
Dyskinesia medications)
X
X
X
X
X
X
X
X
X
X
Has been changed to read:
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9 
Wk 
13 
FUa
Transition to 
Commercial 
Visitsb
Concomitant Medication 
(including anti-PD and 
Dyskinesia medications)
X
X
X
X
X
X
X
X
X
X
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
159
Table 4.  Study Activities
Activity "PEG-J Placement Procedurei" previously read:
PEG-J Placement Procedurei
Has been changed to read:
PEG-J Placement Procedureh


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
160
Table 4.  Study Activities
Activity "Dose Titration Diaryn" previously read:
OMT/LCIG
LCIG Treatment
OMT/LCIG 
Treatment
LCIG 
Treatment 
(Drug 
Dispensing 
Visits Only)
OMT/ 
LCIG 
Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
6
V7 
Wk 
12
Wk 
17
Wk 
22
V8 
Wk 26/ET
V9 
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
Dose Titration Diaryn
X
Has been changed to read:
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9 
Wk 
13 
FUa
Transition to 
Commercial 
Visitsb
Dose Titration Diaryn
X
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
161
Table 4.  Study Activities
Activity "UPDRS II and IIIs" previously read:
OMT/LCIG
LCIG Treatment
OMT/LCIG 
Treatment
LCIG 
Treatment 
(Drug 
Dispensing 
Visits Only)
OMT/ 
LCIG 
Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
6
V7 
Wk 
12
Wk 
17
Wk 
22
V8 
Wk 26/ET
V9 
Wk 
27 
FUa
Transition 
to 
Commercial 
Visitsb
UPDRS II and IIIs
Xt
X
X
X
X
X
Has been changed to read:
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 Screening
V2 
Screening
V3 
Randomization
V4 
NJ/PEG-J 
Placement 
D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9 
Wk 
13 
FUa
Transition to 
Commercial 
Visitsb
UPDRS II and IIIt
X
X
X
X
X
X


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
162
Table 4.  Study Activities
Activity "UDysRS" previously read:
UDysRS
Has been changed to read:
UDysRSs
Table 4.  Study Activities
Activity "mAIMS" previously read:
mAIMS
Has been changed to read:
mAIMSu
Table 4.  Study Activities
Table note "g.," first and second sentence previously read:
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 3, 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.
Has been changed to read:
At Screening Visit 1 and Randomization Visit 3 a full physical examination will be 
performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.  Prior to Visit 3, 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.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
163
Table 4.  Study Activities
Table note "i.," last sentence previously read:
Placement can be done at any time during treatment if indicated for worsening of 
Parkinsonian symptoms not responsive to extra doses.
Has been changed to read:
Additional checks can be done at any time during treatment if indicated for worsening of 
Parkinsonian symptoms not responsive to extra doses.
Table 4.  Study Activities
Table note "p."
Delete:  second and third sentence
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.
Table 4.  Study Activities
Add:  table note "s." and "u."
s.
The subject's expected time of peak dose dyskinesia should be determined during screening and the UDysRS 
should be administered at this time throughout the study.
u.
The mAIMS should be completed following the UDysRS at the subject's expected time of peak dose dyskinesia.
Section 5.3.1.1  Study Procedures
Subsection Unified Dyskinesia Rating Scale UDysRS
Third paragraph previously read:
The dimensions are evaluated through both an investigation and interview carried out by 
the physician/rater and self-administered questionnaire.  The UDysRS assessment will be 
performed by an experienced rater.  Rater training will be provided by the Sponsor as 
appropriate.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
164
Has been changed to read:
The Historical Score is the sum of Parts 1 and 2 and the Objective Score is the sum of 
Parts 3 and 4.  The dimensions are evaluated through both an investigation and interview 
carried out by the physician/rater and self-administered questionnaire.  The UDysRS 
assessment will be performed by an experienced rater.  Rater training will be provided by 
the Sponsor as appropriate.  The subject's expected time of peak dose dyskinesia should 
be determined during screening and the UDysRS should be administered at this time 
throughout the study.
Section 5.3.1.1  Study Procedures
Subsection Unified Dyskinesia Rating Scale UDysRS
Fourth paragraph, second sentence previously read:
The videotape will be transmitted to the central rater for scoring of Parts 3 and 4.
Has been changed to read:
The videotape will be transmitted to the Central Blinded Rater for scoring of Parts 3 and 
4.
Section 5.3.1.1  Study Procedures
Subsection Unified Dyskinesia Rating Scale UDysRS
Delete:  seventh paragraph
A Blinded Central Rater will receive the videotape of the UDysRS and will score the 
videotaped assessment of Parts 3 and 4.  A scoring summary will be electronically 
submitted back to site.
Section 5.3.1.1  Study Procedures
Subsection Modified Abnormal Involuntary Movement Scale (mAIMS)
Last paragraph previously read:
The assessments for mAIMS will be obtained as per the times indicated in Table 4.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
165
Has been changed to read:
The assessments for mAIMS should be completed following the UDysRS at the subject's 
expected time of peak dose dyskinesia as per the times indicated in Table 4.
Section 5.3.1.2  Rater Requirements 
Subsection Site Rater Training Requirements
First paragraph
Add:  new second sentence
The UDysRS Parts 1 and 2 will be assessed and scored by site raters who are qualified 
based on MDS training.
Section 5.3.1.2  Rater Requirements 
Subsection Blinded Rater Training Requirements
Subsection title previously read:
Blinded Rater Training Requirements
Has been changed to read:
Blinded Central Rater Training Requirements
Section 5.3.1.2  Rater Requirements 
Subsection Blinded Rater Training Requirements
First paragraph previously read:
The UDysRS will be assessed and scored by experienced blinded central raters who are 
qualified based on MDS training.
Has been changed to read:
The objective portion of the UDysRS (Parts 3 and 4) will be assessed and scored by 
experienced blinded central raters who are qualified based on MDS training.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
166
Section 5.3.3.2  Additional Efficacy and Health Outcome Variables
Subsection Additional Efficacy Endpoints are:
Add:  new first bullet
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
Section 5.3.3.2  Additional Efficacy and Health Outcome Variables
Subsection Additional Health Outcome Endpoints:
Delete:  last bullet
Percentage (%) of CGI-C responders ("minimally improved," "much improved" or "very 
much improved")
Section 5.5.1.2  LCIG
Subsection Nasojejunal Tube
First paragraph, last sentence previously read:
The NJ should be inserted by a gastroenterologist proceduralist, surgeon or interventional 
radiologist.
Has been changed to read:
The NJ should be inserted by a gastroenterologist proceduralist, surgeon, interventional 
radiologist or experienced nurse if done via the passive method.
Section 5.5.3  Method of Assigning Subjects to Treatment Groups
Second paragraph, first sentence previously read:
At Screening during Visit 1, each subject will be assigned a unique 5-digit number by the 
IRT system.  
Has been changed to read:
At Screening during Visit 1, each subject will be assigned a unique 4-digit number by the 
IRT system.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
167
Section 5.5.5  Blinding
Last paragraph, first, second, third, and fourth sentence previously read:
Blinded central raters will be used to administer the UDysRS, the primary efficacy 
endpoint for this study.  Assessment obtained at V3 will serve as the baseline for clinical 
assessment.  The scales will also be performed at Visits Week 2, 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.
Has been changed to read:
Central blinded raters will be used to rate Parts 3 and 4 of the UDysRS, the primary 
efficacy endpoint for this study.  Assessment obtained at V3 will serve as the baseline for 
clinical assessment.  The scales will also be performed at Weeks 2, 4, 8, and 12.  The 
scoring for Parts 3 and 4 are to be performed by a trained central blinded 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.  
Section 5.5.7  Drug Accountability
Third paragraph, second sentence previously read:
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.
Has been changed to read:
This will be documented by the Investigator or designee 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.  


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
168
Section 5.6.2  Appropriateness of Measurements
Subsection UDysRS Validation and Psychometric Properties
First paragraph, last sentence previously read:
Convergent, content and discriminant validity have also not been assessed.
Has been changed to read:
Convergent and discriminant validity have also not been assessed.
Section 5.6.2  Appropriateness of Measurements
Subsection UDysRS Validation and Psychometric Properties
Last paragraph previously read:
In conclusion, the UDysRS is a comprehensive rating tool to measure dyskinesia and has 
been studied clinimetrically as both a consistent and reliable measure.  The scale however 
has not been assessed for construct and content validity.
Has been changed to read:
The UDysRS is a comprehensive rating tool to measure dyskinesia and has been studied 
clinimetrically as both a consistent and reliable measure.  The scale however has not been 
assessed for construct and content validity.
Additional analysis will be performed to provide evidence on the construct validity of the 
UDysRS.  Convergent validity will be evaluated by Spearman rank correlations between 
UDysRS total score (and sub-scores) and the AIMS score and Parkinson's Disease Diary 
assessment of severity of dyskinesia.  In addition, the association with indirectly related 
constructs to dyskinesia, the PDQ-8 total score (measuring the PD-specific health status 
and quality of life) as well as the UPDRS scores for Parts II – III will be determined.  
Correlations ≥ 0.30 are hypothesized to support convergent validity.  Discriminative 
validity will be explored by sub-group analyses.  The UDysRS total score will be 
stratified by the Hoehn and Yahr stages and tested using the Kruskal-Wallis test.


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
169
Section 7.0  Protocol Deviations
Contact information previously read:
Primary Contact:
Avenida de Burgos, 91
28050 MADRID
SPAIN
Office:
Mobile:
Fax:
Alternate Contact:
1 North Waukegan Road
North Chicago, IL 60064
USA
Office:
Fax:
Has been changed to read:
Primary Contact:
Avenida de Burgos, 91
28050 MADRID
SPAIN
Email:
Office:
Mobile:
Fax:
Alternate Contact:
1 North Waukegan Road
North Chicago, IL 60064
USA
Email:
Office:
Mobile
Fax:
Section 8.1.3.3  Additional Efficacy and Health Outcomes Analyses
First paragraph, first bullet previously read:
"ON" time without troublesome dyskinesia and "ON" time without dyskinesia as 
measured by the PD Diary
Has been changed to read:
●
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores


Levodopa-Carbidopa Intestinal Gel/Carbidopa Levodopa Enteral Suspension
M15-535 Protocol Amendment 1
EudraCT 2016-001403-23
170
●
"ON" time with troublesome dyskinesia and "ON" time without dyskinesia as 
measured by the PD Diary
Section 8.1.3.3  Additional Efficacy and Health Outcomes Analyses
Last paragraph, last sentence previously read:
To evaluate this assumption, the MMRM analysis of the primary and secondary variables 
will be repeated using only subjects who completed the planned treatment period.
Has been changed to read:
To evaluate this assumption, the MMRM analysis of the primary and secondary variables 
will be repeated using only subjects who completed the planned treatment period and 
additional sensitivity analyses to evaluate the impact of missing data on the primary 
efficacy results will be performed.  These sensitivity analyses will be described in the 
Statistical Analysis Plan (SAP).
Section 9.3  Subject Information and Consent
First paragraph, first sentence previously read:
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  
Has been changed to read:
The Investigator or his/her representative will explain the nature of the study to the 
subject.  The subject must be able to understand the nature of the study and have the 
opportunity to have any questions answered by the Investigator.

SAP_001.pdf: 
Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M15-535
An Open-Label, Randomized 12 Week Study 
Comparing Efficacy of Levodopa-Carbidopa 
Intestinal Gel/Carbidopa-Levodopa Enteral 
Suspension and Optimized Medical Treatment on 
Dyskinesia in Subjects with Advanced Parkinson's 
Disease
DYSCOVER (DYSkinesia COmparative interventional 
trial on Duodopa VERsus oral medication)
Date:  21 May 2018
Version 1.0
NCT02799381


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
2
2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 5
4.3
Sample Size............................................................................................ 8
4.4
Interim Analysis ..................................................................................... 8
4.5
Efficacy and Health-Related Outcome Measures .................................... 8
4.5.1
Motor Symptoms/Motor Complications.................................................. 8
4.5.2
Health-Related Outcomes....................................................................... 9
4.6
Safety Measures ..................................................................................... 9
5.0
Analysis Populations ........................................................... 10
6.0
Analysis Conventions .......................................................... 10
6.1
Statistical Significance ......................................................................... 10
6.2
Definition of Study Epochs and LCIG Treatment Period 
Reference Variables ............................................................................. 11
6.3
Definition of Baseline and Final Observation ....................................... 12
6.4
Analysis by Planned Visit for PD Diary Variables ................................ 13
6.5
Analysis by Planned Visit for Non-Diary Variables.............................. 14
6.6
Adverse Event Analysis by Study Week............................................... 16
6.7
Derived Datasets .................................................................................. 16
7.0
Subject Disposition, Baseline Characteristics and 
Concomitant Medications ...................................................17
7.1
Subject Disposition............................................................................... 17
7.2
Demographic and Baseline Characteristics ........................................... 18
7.3
Medical History.................................................................................... 19
7.4
Prior and Concomitant Medications...................................................... 19
8.0
Treatment Exposure and Compliance ...............................20
8.1
Duration of Treatment and PEG-J Exposure......................................... 21
8.2
Duration of NJ Period........................................................................... 23


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
3
8.3
LCIG Daily Prescribed Dose ................................................................ 23
8.4
Total Daily Levodopa Dose.................................................................. 24
8.5
Daily Treatment Duration..................................................................... 25
8.6
Tube Replacements .............................................................................. 25
8.7
Duration of Initial LCIG Titration ........................................................ 25
9.0
Efficacy and Health Outcome Analysis.............................. 26
9.1
General Considerations......................................................................... 26
9.2
Primary Efficacy Analysis.................................................................... 26
9.3
Additional Efficacy Analyses ............................................................... 28
9.4
Calculation of Efficacy and Health Outcome Variable.......................... 29
9.5
Handling of Multiplicity....................................................................... 33
9.6
Efficacy Subgroup Analysis ................................................................. 33
10.0
Safety Analysis.....................................................................34
10.1
General Considerations......................................................................... 34
10.2
Analysis of Adverse Events.................................................................. 34
10.2.1
Adverse Event Overview...................................................................... 35
10.2.2
Adverse Event Incidence ...................................................................... 36
10.2.3
Adverse Events of Special Interest........................................................ 38
10.2.4
Adverse Events by Subgroup................................................................ 38
10.2.5
Listings of Adverse Events................................................................... 39
10.3
Analysis of Laboratory Tests................................................................ 39
10.3.1
Analysis of Mean Changes for Laboratory Tests................................... 40
10.3.2
Shifts Between Normal and Abnormal for Laboratory Tests................. 40
10.3.3
Potentially Clinically Significant (PCS) Laboratory Values .................. 41
10.4
Analysis of Vital Signs and Weight ...................................................... 41
10.4.1
Vital Sign and Weight Mean Changes .................................................. 42
10.4.2
Shifts in BMI Category......................................................................... 42
10.4.3
Potentially Clinically Significant (PCS) Vital Sign and Weight 
Values .................................................................................................. 42
10.5
Analysis of Electrocardiogram (ECG) Variables................................... 43
10.5.1
ECG Mean Changes ............................................................................. 43
10.5.2
Potentially Clinically Significant (PCS) ECG Values ........................... 44
10.6
Analysis of Sleep Attack Questions ...................................................... 44


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
4
10.7
Analysis of Minnesota Impulsive Disorders Interview (MIDI).............. 44
10.8
Analysis of Columbia-Suicide Severity Rating Scale (C-SSRS)............ 46
11.0
Special Statistical Topics..................................................... 46
12.0
Summary of Changes .......................................................... 46
13.0
Appendices...........................................................................47
List of Tables
Table 1.
Primary and Secondary Efficacy Variables, and Derivations................. 30
List of Figures
Figure 1.
Study Design Schematic......................................................................... 7
List of Appendices
Appendix A.
Study Activities.................................................................................... 48
Appendix B.
Potentially Clinically Significant Laboratory Values ............................ 53
Appendix C.
Criteria for Potentially Clinically Significant Vital Sign and 
Weight Values...................................................................................... 54
Appendix D.
Criteria for Potentially Clinically Significant ECG Values.................... 55


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
5
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 M15-535 with a protocol dated 26 May 2016 incorporating one amendment 
(original protocol:  03 May 2016, Amendment 1:  26 May 2016).  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 interventional study is to examine the effect of LCIG 
treatment relative to that of Optimized Medical Treatment (OMT) on dyskinesia as 
measured by the Unified Dyskinesia Rating Scale (UDysRS) Total Score.
The Secondary objective is to assess the effect of LCIG treatment relative to that of OMT 
on dyskinesia as measured by PD Diaries, motor symptoms, motor complications, health-
related outcome measures, safety and tolerability.
4.2
Design Diagram
This is a Phase 3b, open-label, randomized multicenter 12 week study assessing the 
efficacy of LCIG treatment compared to OMT on dyskinesia in subjects with Advanced 
Parkinson's Disease.
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 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
6
assessed to determine eligibility.  The duration of the Screening Period will 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 dyskinesia.  
All anti-PD medications and medications to treat dyskinesia 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 anti-PD 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, 4, 8, and 12.  Subjects randomized to LCIG treatment must discontinue all other 
anti-PD medications other than amantadine (e.g., dopamine agonists, COMT-inhibitors, 
MAO-B inhibitors, anti-cholinergics, and subcutaneous apomorphine, etc.) prior to LCIG 
treatment initiation on Day 1 (V4); these medications should be tapered off within 14 days 
after randomization according to the discretion of the Investigator.  With the exception of 
apomorphine, levodopa containing formulations or amantadine, these medications may be 
restarted if indicated by the subject's individual condition, but not within the first 28 days 
after LCIG treatment initiation.  Optional nasojujunal (NJ) 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, 4, 8, and 12.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
7
Figure 1.
Study Design Schematic
Part 3:  Follow-up period.  The OMT subjects will not have a follow-up visit (V9).  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.  For LCIG subjects who elect to discontinue LCIG and not continue 
with commercially available product, a V9 will be conducted 1 week after PEG-J removal 
and the SAE/AE follow-up period will be up until 30 days after PEG-J removal.  For 
LCIG treatment subjects who will transition to commercial product, the SAE/AE follow-
up period will be up until 30 days after the transition.  For study subjects in the LCIG 
group 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 12 will be scheduled to monitor subject 
safety and allow for drug resupply until the subject transfers to commercial LCIG.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
8
4.3
Sample Size
Approximately 60 subjects will be enrolled into the study and randomized in a 1:1 ratio to 
either optimized medical treatment (OMT) or LCIG treatment.  Subject randomization 
will be stratified by country.  For sample size determination, it is assumed that the 
difference of improvement is 10 points on UDysRS total score between the LCIG 
treatment group and OMT group based on results reported by Pahwa et al (2015).  The 
pooled standard deviation is assumed to be 12 based on results reported by Goetz et al 
(2013).  Assuming that the treatment group difference is 10 points and the pooled standard 
deviation is 12, 27 subjects per group will have 85% power to declare statistical 
significance on the primary endpoint at a two-sided significance level of 0.050 based on 
calculations using nQuery + nTerim 4.0.  It is further assumed that 10% of randomized 
subjects in either treatment group will not provide post-randomization efficacy 
assessment.  Therefore the total planned enrollment is decided to be approximately 
60 subjects.
4.4
Interim Analysis
After all randomized subjects have completed the 12-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
Motor Symptoms/Motor Complications
Motor symptoms will be assessed by the following measures.
●
Unified Dyskinesia Rating Scale (UDysRS)
●
Parkinson's Disease Diary (PD Diary):  normalized average daily hours of OFF 
time, ON time with troublesome dyskinesia, ON time without troublesome 
dyskinesia


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
9
●
Unified Parkinson's Disease Rating Scale (UPDRS) Part III
●
Modified Abnormal Involuntary Movement Scale (mAIMS)
4.5.2
Health-Related Outcomes
Health-related outcomes will be assessed by the following measures.
●
UPDRS Part II
●
Parkinson's Disease Questionaire-8 (PDQ-8)
●
King's PD Pain Scale
●
Clinical Global Impression of Severity (CGI-S)
●
Clinical Global Impression of Change (CGI-C)
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
●
Electrocardiogram
●
Vital signs and weight
●
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Minnesota Impulsive Disorders Interview (MIDI)
●
Sleep Attacks Questionnaire (SAQ)


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
10
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.
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 following PEG-J placement.  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 a study device (NJ 
and/or PEG-J) placement procedure.  The safety dataset will be used to summarize safety 
data during the OMT and LCIG treatment period.
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.  
If the primary efficacy variable UDysRS total score is statistically significant, each of the 
secondary efficacy variables will be tested using the fixed sequence below as a 
gatekeeping procedure and at α level of 0.050.  Testing will cease at the point that a 
secondary variable fails to demonstrate statistical significance.
●
"ON" time without troublesome dyskinesia as measured by the PD Diary


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
11
●
Parkinson's Disease Questionaire-8 (PDQ-8) summary index
●
Clinical Global Impression of Change (CGI-C) Score
●
UPDRS Part II Score
●
"OFF" time as measured by the PD Diary
●
UPDRS Part III Score
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
Device Before (LCIG 
group only)
Open
Transition (LCIG group 
only)
Device After (LCIG 
group only)
Off


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
12
For subjects in 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 the treatment start 
reference date (REFDT) 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 will be considered the 
end of the LCIG treatment period and the following day will be the post-treatment start 
reference date (REFEDT).  For subjects in the OMT group, the date after randomization 
will be considered the start of treatment period and will be the treatment start reference 
date (REFDT).  The date of the final visit will be considered the end of the OMT 
treatment period and the following day will be the post-treatment start reference date 
(REFEDT).
Study Days will be calculated based on the treatment start reference date (REFDT).  For 
time points before REFDT, the Study Day = time point – REFDT.  For time points on or 
after REFDT, the Study Day = time point – REFDT + 1.  Thus, the Study Day is a 
negative value when the time point of interest is prior to REFDT and the Study Day is a 
positive value when the time point of interest is on or after REFDT.  There is no Study 
Day 0.  The Study Day will be labeled as Rx Day on the data listings.  RxEnd Day is 
calculated for each post-treatment time point as the number of days between REFEDT and 
the specific time point:  RxEnd Day = date of time point – REFEDT + 1.
6.3
Definition of Baseline and Final Observation
Baseline for PD Diary variables will be the average of the last 3 valid diaries completed 
on or before the day of randomization.  Baseline for all efficacy, health outcome and 
safety measures, other than the PD Diary, will be defined as the last non-missing 
observation that is on or before the day of randomization.
The final visit for PD Diary variables for the OMT group will be the average of the last 
3 valid diaries that are after the day of randomization during the 12-week Treatment 
Period.  The final visit for PD Diary variables for the LCIG group will be the average of 
the last 3 valid diaries that are after the date of the first LCIG infusion following PEG-J 
placement and on or before the date of the last LCIG infusion during the 12-week 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
13
Treatment Period.  The final visit for efficacy and health outcome measure, other than PD 
Diary variables, for the OMT group will be defined as the last non-missing observation 
that is after the day of randomization during the 12-week Treatment Period.  The final 
visit for efficacy and health outcome measures, other than PD Diary variables, 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 12-week Treatment Period.
For subjects who discontinue LCIG treatment during the 12-week Treatment Period or 
complete the 12-week Treatment Period but not going to transit to commercial product, 
the final visit for safety assessments will be defined based on the final removal of all 
LCIG devices and will be 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.  For subjects who transit to commercial product, the 
final visit will be the last non-missing observation during the 12-week Treatment Period 
in the database.  Safety assessments on the date of the first PEG-J placement procedure 
that do not have a time of assessment or sample collection recorded will be assumed to be 
post-procedure.  For subjects in the OMT group, the final visit for safety assessments will 
be defined as the last non-missing observation that is after the day of randomization 
during the 12-week Treatment Period.
6.4
Analysis by Planned Visit for PD Diary Variables
The PD Diary will be used by the subject and/or their caregiver to record parkinsonian 
symptoms on the 3 days prior to clinic visits as indicated in the Schedule of Study 
Activities.  The total daily awake time will be calculated for each diary as described in 
Section 9.4.  Only diaries with at least 12 hours of awake time will be considered valid 
and included in the analyses.
The PD Diary is planned to be completed on each of 3 days prior to selected scheduled 
visits.  It is expected that all 3 diary days will fall in the same visit window as long as the 
subject is on schedule.  However, there may be rare instances where the timing of a 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
14
subject's visit schedule shifts due to unforeseen circumstances.  To ensure that each 
adjacent diary day will be assigned to the same visit window, each diary day will be 
linked to the nearest scheduled visit that occurred after the date on which the diary was 
completed.  The PD diary data will be assigned to a visit window based on the date of this 
scheduled visit.
Assessment
Planned Visit
Nominal Study Day
Study Day Rangea
PD Diary
Baseline
≤ date of randomization
Week 2
14
2 – 21
Week 4
28
22 – 42
Week 8
56
43 – 70
Week 12
84
≥ 71
a.
For subjects in LCIG group, all post-baseline PD Diaries must also be after start of LCIG infusion through PEG-J 
and on or before the date of the last LCIG infusion in the 12-week Treatment Period.
The valid diary days (at least 12 awake hours) will be used to compute the average daily 
times.  For post-baseline visits, the valid diary days must be within 7 days of the 
scheduled visit but not on or after the day of the scheduled visit.  If more than 3 valid 
diary days are available, the last 3 days in each visit window will be used.  If only 1 or 
2 valid diary days are available prior to a scheduled visit, data from the available days will 
be used to calculate the average daily times.  Subjects that do not have any valid diary 
days for a visit will have the average daily times set to missing for that visit.
6.5
Analysis by Planned Visit for Non-Diary Variables
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 the 12-week Treatment Period.  Assessments 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
15
on the day of first day of LCIG infusion via PEG-J are not planned and will not be 
included in the analysis.
Assessment
Planned Visit
Nominal Study Day
Study Day Rangea
UDysRS, UPDRS, 
mAIMS, CGI-C
Baseline
≤ date of randomization
Week 2
14
2 – 21
Week 4
28
22 – 42
Week 8
56
43 – 70
Week 12
84
≥ 71
PDQ-8
Baseline
≤ date of randomization
Week 8
56
2 – 70
Week 12
84
≥ 71
King's PD Pain Scale
Baseline
≤ date of randomization
Week 4
28
2 – 42
Week 8
56
43 – 70
Week 12
84
≥ 71
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 12-week Treatment Period.
The following Study Day windows will be used to assign safety assessments during the 
12-week Treatment Period to planned study visits.
Assessment
Planned Visit
Nominal Study Day
Study Day Rangea
Vital signs and weight, 
MIDI, Sleep Attacks 
Questionnaire, C-SSRS
Baseline
≤ date of randomization
Week 2
14
2 – 21
Week 4
28
22 – 42
Week 8
56
43 – 70
Week 12
84
≥ 71
Week 13 FUb
91
2 ≤ RxEnd Days
Clinical labs and 
Electrocardiograms, 
Special labs
Baseline
≤ date of randomization
Week 8
56
1 – 70
Week 12
84
≥ 71
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 do not transit to commercial product or no more than 1 day after the final Study M15-535 
LCIG infusion during 12-week Treatment Period for subjects who transit to commercial product.
b.
Applicable only to LCIG subjects who will not continue on commercial product.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
16
For LCIG subjects who enter the Transition Period, vital signs and weight, special labs, 
C-SSRS and MIDI will be assessed every 12 weeks.
6.6
Adverse Event Analysis by Study Week
Treatment-emergent adverse events during the 12-week Treatment Period will be assigned 
to study week intervals based on the Study Day of onset as follows.
Study Week(s)
Study Day Range
Week 1
1 – 7
Week 2
8 – 14
Week 3
15 – 21
Week 4
22 – 28
Weeks 5 – 8
29 – 56
Weeks 9 – 12
≥ 57
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 for the Safety Dataset:  For LCIG subjects, one record 
per subject for each 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 UDysRS, PDQ-8, CGI-C, 
UPDRS Part II, UPDRS Part III, mAIMS, King's PD Pain Scale, and "ON" 
time without troublesome dyskinesia, "OFF" time, "ON" time with 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
17
troublesome dyskinesia and "ON" time without dyskinesia as measured by PD 
Diary.
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 12 weeks of treatment in 
OMT group; randomized to LCIG group, prematurely discontinued treatment from LCIG 
group, completed the planned 12 weeks of treatment in LCIG group.  The total number of 
subjects in LCIG group in each of the following categories as well as the number at each 
site will be presented:  Randomized, No NJ/PEG-J placed, NJ placed, prematurely 
discontinued treatment during NJ, PEG-J placed, prematurely discontinued treatment 
during 12-week Treatment Period, prematurely discontinued treatment during commercial 
transition, transit to commercial.
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 first 12 weeks 
of treatment for both treatment groups, during the transition period (LCIG group only) 
and during the entire study (including first 12 weeks and transition period for LCIG group 
only) 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.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
18
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
●
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


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
19
○
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 
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 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
20
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 12-week Treatment Period (start date before or on the last date of 
the 12-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 12-week Treatment Period (start date before or 
on the last date of the 12-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 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.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
21
8.1
Duration of Treatment and PEG-J Exposure
During the 12-Week Treatment Period
The duration of study drug exposure for LCIG subjects and the duration of study 
participation for OMT subjects during the 12-week Treatment Period will be summarized 
with descriptive statistics (number of subjects with non-missing data, mean, standard 
deviation, median, minimum and maximum).  The duration of LCIG study drug exposure 
will be calculated for each subject as the date of the last infusion of LCIG study drug 
during the 12-week Treatment Period minus the date of the first infusion 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 minus the date of randomization.
The duration of PEG-J exposure for LCIG subjects during the 12-week Treatment Period 
will be summarized with descriptive statistics (number of subjects with non-missing data, 
mean, standard deviation, median, minimum and maximum).  For subjects who don't have 
Transition Period, the duration of PEG-J exposure for each subject will be calculated as 
the date of their final PEG-J removal or the date of their last infusion of LCIG study drug 
during the 12-week Treatment Period if there is no PEG-J removal minus the date of their 
initial PEG-J placement + 1. For subjects who have Transition Period, the duration of 
PEG-J exposure for each subject will be calculated as the date of their last infusion of 
LCIG study drug during the 12-week Treatment Period minus the date of their initial 
PEG-J placement + 1.
The number and percentage of subjects in each of the following exclusive duration 
categories during the 12-week Treatment Period will be summarized for LCIG infusion 
exposure and PEG-J 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 days (≥ 9 weeks)


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
22
In addition, duration of exposure during the 12-week Treatment Period 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 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 Transition Period
The duration of study drug exposure for LCIG subjects during the Transition Period will 
be summarized with descriptive statistics (number of subjects with non-missing data, 
mean, standard deviation, median, minimum and maximum).  The duration of LCIG study 
drug exposure will be calculated for each subject as the date of the last infusion of LCIG 
study drug during the Transition Period minus the date of the last infusion of LCIG study 
drug during the 12-week Treatment Period.
The duration of PEG-J exposure for LCIG subjects during the Transition Period will be 
summarized with descriptive statistics (number of subjects with non-missing data, mean, 
standard deviation, median, minimum and maximum).  For subjects with a PEG-J tube 
removal after their last infusion of LCIG study drug during the Transition 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 last infusion of LCIG study drug during the 
12-week Treatment Period.  For subjects without a PEG-J tube removal after their last 
infusion of LCIG study drug during the Transition Period, the duration of PEG-J exposure 
for each subject will be calculated as the date of their final participation in Study M15-535 
(last contact or visit date) minus the date of their last infusion of LCIG study drug during 
the 12-week Treatment Period.
Overall
The overall duration of study drug exposure for LCIG subjects and the overall duration of 
study participation for OMT subjects will be summarized with descriptive statistics 
(number of subjects with non-missing data, mean, standard deviation, median, minimum 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
23
and maximum).  The overall duration of LCIG study drug exposure will be calculated for 
each subject as the date of the last infusion of LCIG study drug minus the date of the 
first infusion of LCIG study drug plus 1.  The overall duration of study participation for 
OMT subjects will be calculated for each subject as the date of the last visit minus the 
date of randomization.
The overall duration of PEG-J exposure for LCIG subjects will be summarized with 
descriptive statistics (number of subjects with non-missing data, mean, standard deviation, 
median, minimum and maximum).  The overall duration of PEG-J exposure for each 
subject will be calculated as the date of their final PEG-J removal or the date of their final 
participation in Study M15-535 (last contact or visit date) if there is no PEG-J removal 
minus the date of their initial PEG-J placement + 1.
8.2
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).
8.3
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 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
24
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
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.
8.4
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 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,


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
25
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.
8.5
Daily Treatment Duration
The LCIG pump start time and end time at each clinic visit will be recorded on the Dosing 
Diary 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.
8.6
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 M15-535 PEG-J tube exposure.  Subjects with a PEG-J tube 
removal after their last infusion of Study M15-535 study drug will be censored at this 
final tube removal date.  Subjects without a PEG-J tube removal after their last infusion of 
Study M15-535 study drug will be censored on the date of their final participation in 
Study M15-535 (last contact or visit date).
8.7
Duration of Initial LCIG Titration
Duration of initial LCIG titration for each subject will be calculated as the date of the 
first optimized prescription minus the first LCIG infusion date + 1.  The first LCIG 
infusion date will be recorded on the Study Drug Administration eCRF.  The current 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
26
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).
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.
9.2
Primary Efficacy Analysis
UDysRS Total Score
The UDysRS was developed to evaluate dyskinesia in Parkinson's disease.  It contains 
two primary sections with 26 questions:
Historical [Part 1 (On-Dyskinesia) and Part 2 (Off-Dystonia)]
Objective [Part 3 (Impairment) and Part 4 (Disability)]
Part 1 contains 11 questions about the on time dyskinesia and the impact of on-dyskinesia 
on experiences of daily living.  Part 2 contains 4 questions of off-dystonia rating.  Part 3 
contains 7 questions about objective evaluation of dyskinesia impairment and Part 4 
contains 4 questions regarding dyskinesia disability.  Each question is scored with respect 
to severity, which is rated on a scale where 0 = normal, 1 = slight, 2 = mild, 3 = moderate 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
27
and 4 = severe.  The UDysRS total score is obtained by summing the item scores, ranging 
from 0 to 104.
The primary efficacy variables will be the change from baseline to Week 12 in the 
UDysRS total scores.  It will be estimated using PROC MIXED and a mixed-effect model 
repeated measures (MMRM) for the change from baseline to each scheduled post-baseline 
visit.  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 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 12 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 12 for LCIG group in the 
UDysRS total score and μOMT is the mean change from baseline to Week 12 for OMT 
group in the UDysRS total score.  The statistical tests at other visits will be considered 
secondary.
The change in the UDysRS total score to each planned visit and to the final visit will also 
be summarized by the following descriptive statistics:  number of non-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 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
28
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.
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 UDysRS 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 UDysRS.
Analysis of Secondary Efficacy Variables
The MMRM model and the descriptive statistic summary described for the UDysRS total 
score will also be used to evaluate the change from baseline to Week 12 in each of the 
following efficacy endpoints (with the exception of the CGI-C, which the score itself 
shows the changes):
●
"ON" time without troublesome dyskinesia as measured by the PD Diary
●
Parkinson's Disease Questionaire-8 (PDQ-8) summary index
●
Clinical Global Impression of Change (CGI-C) Score
●
UPDRS Part II Score
●
"OFF" time as measured by the PD Diary
●
UPDRS Part III Score
PD Diary variables will be normalized to a 16 hour awake time and the time recorded by 
the subject on the 3 diaries completed prior to each visit will be averaged.
For CGI-C, an ANCOVA model containing treatment and country as the main effects and 
baseline CGI-S as covariate will be carried out.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
29
"ON" time without troublesome dyskinesia as measured by the PD Diary, PDQ-8 
summary index, CGI-C score, UPDRS Part II and Part III score, and "OFF" time as 
measured by the PD Diary are key secondary endpoints.  If the primary efficacy variable 
is statistically significant, each of the secondary variables will be tested using the fixed 
sequence above as a gatekeeping procedure and at α level of 0.050.  Testing will cease at 
the point that a secondary variable fails to demonstrate statistical significance.
All secondary efficacy variables will be summarized by the number of subjects with non-
missing data, mean, standard deviation, median, minimum and maximum.
Analysis of Additional Efficacy and Health Variables
Efficacy will also be assessed using the following additional measures:
●
UDysRS Historical Score, Objective Score and Parts 1 through 4 Scores
●
"ON" time with troublesome dyskinesia and "ON" time without dyskinesia as 
measured by the PD Diary
●
mAIMS
Health outcomes will also be assessed using the following additional measures:
●
King's PD Pain Scale
●
Percentage (%) of CGI-C responders (response of "minimally improved," 
"much improved" or "very much improved")
Continuous endpoints will be analyzed with the same MMRM model as the primary 
analysis.  Categorical endpoints will be analyzed with a Fisher's exact test.
9.4
Calculation of Efficacy and Health Outcome Variable
The primary and secondary efficacy variables derived from the above measures are 
presented in Table 1.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
30
Table 1.
Primary and Secondary Efficacy Variables, and Derivations
Instrument
Efficacy Variable
Derivation
Range/Direction
UDysRS:  26 questions, Part 1 (Questions 1 – 11), 
Part 2 (Questions 12 – 15), Part 3 (Questions 16 – 22), 
and Part 4 (Questions 23 – 26).  All questions are 
5-point (0 – 4).  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.
Part 1 score
Sum of Questions 1 – 11
0 – 44/lower value desirable
Part 2 score
Sum of Questions 12 – 15
0 – 16/lower value desirable
Part 3 score
Sum of Questions 16 – 22
0 – 28/lower value desirable
Part 4 score
Sum of Questions 23 – 26
0 – 16/lower value desirable
Historical score
Sum of Part 1 score and Part 2 score
0 – 60/lower value desirable
Objective score
Sum of Part 3 score and Part 4 score
0 – 44/lower value desirable
Total score
Sum of Part 1, Part 2, Part 3, and Part 4 scores
0 – 104/lower value desirable
PD Diary:  48 entries each diary day starting at 6:00 am 
and goes thru 6:00 am on the following chronological 
day, each represents 0.5 hour.  Subjects were instructed 
to record whether "Asleep," "Off," "On without 
dyskinesia," "On with non-troublesome dyskinesia" or 
"On with troublesome dyskinesia" for each 0.5 hour.
Daily awake time (hr) = time spent in "Off," "On 
without dyskinesia," "On with non-troublesome 
dyskinesia" or "On with troublesome dyskinesia." 
The "Off" and various "On" times are normalized to 
16-hour awake period based a typical person's day.
Only diaries with at least 12 hours of daily awake time 
will be considered valid and used in the analysis.
Normalized "ON" time 
without troublesome 
dyskinesia
(Absolute "On" time without dyskinesia + 
Absolute "On" time with non-troublesome 
dyskinesia)/Daily awake time * 16
0 – 16 hours/higher value desirable
Normalized "OFF" time
Absolute "Off" time/Daily awake time * 16
0 – 16 hours/lower value desirable
Normalized "ON" time with 
troublesome dyskinesia
Absolute "On" time with troublesome 
dyskinesia/Daily awake time * 16
0 – 16 hours/lower value desirable
Normalized "ON" time 
without dyskinesia
Absolute "On" time without dyskinesia/Daily 
awake time * 16
0 – 16 hours/higher value desirable


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
31
Table 1.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
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
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
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 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


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
32
Table 1.
Primary and Secondary Efficacy Variables, and Derivations (Continued)
Instrument
Efficacy Variable
Derivation
Range/Direction
mAIMS:  6 questions, all questions are 5 points (0 – 4).
There is no imputation of missing responses.
mAIMS score
Sum of Questions 1 – 6
0 – 24/lower value desirable
King's PD Pain Scale (KPPS):  14 items addressing the 
following 7 domains (musculoskeletal pain, chronic 
pain, fluctuation-related pain, nocturnal pain, oro-facial 
pain, discoloration, oedema/swelling, 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 to12.
King's PD Pain Scale score
Sum of severity x frequency for all 14 items.  
The KPPS 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
Musculoskeletal Pain
Severity × frequency for item 1
0 – 12/lower value desirable
Chronic Pain
Sum of severity × frequency for item 2 and 3
0 – 24/lower value desirable
Fluctuation-related Pain
Sum of severity × frequency for item 4 – 6
0 – 36/lower value desirable
Nocturnal Pain
Sum of severity × frequency for item 7 and 8
0 – 24/lower value desirable
Oro-facial Pain
Sum of severity× frequency for item 9 – 11
0 – 36/lower value desirable
Discoloration, 
Oedema/Swelling
Sum of severity × frequency for item 12 and 
13
0 – 24/lower value desirable
Radicular Pain
Severity x frequency for item 14
0 – 12/lower value desirable


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
33
9.5
Handling of Multiplicity
If the primary efficacy variable is statistically significant, each of the key secondary 
variables will be tested using the fixed sequence in Section 9.3 as a gatekeeping procedure 
and at α level of 0.050.  Testing will cease at the point that a secondary variable fails to 
demonstrate statistical significance.
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 
UDysRS 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 UDysRS total scores will also be 
prepared for each subgroup stratum.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
34
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 
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) is defined as any adverse event with onset 
during the treatment period or within 30 days of the end of the treatment period:
●
For the OMT group this includes all adverse events with onset after the day of 
randomization and within 30 days following the last visit.
●
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 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
35
following the last study tube removal, or no more than 30 days following the 
last LCIG infusion if there is no final device removal in the study.
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 12-week Treatment 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
The number and percentage of subjects experiencing one or more adverse events in the 
following adverse event categories during the 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)


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
36
●
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.
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 12-week Treatment Period will be 
summarized for each treatment group and for overall subjects by primary SOC and PT for 
overall treatment interval.
●
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 Transition Period will be summarized for 
LCIG subjects who enter the Transition Period by primary SOC and PT.
●
Any TEAE
●
Any serious TEAE
●
Any TEAE that led to discontinuation of study drug


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
37
The number and percentage of subjects experiencing one or more TEAEs during the 
12-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 for overall treatment interval.  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 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 
12-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 for 
overall treatment interval.  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 during the 12-week Treatment Period will be 
summarized by PT for overall treatment period interval and overall.  The PTs will be 
presented by decreasing frequency overall.
●
Any TEAE
●
Any TEAE that was moderate or severe


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
38
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).  This 
summary will be done for the LCIG group only.
●
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 12-week Treatment Period will be summarized for each treatment group 
and for overall subjects by primary SOC and PT for overall treatment period interval.  
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 the 12-week 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) 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
39
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)
●
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.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
40
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 12-week 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 
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 baseline to each planned visit and to the minimum, 
maximum and final value during the Transition Period will be presented for each 
continuous special laboratory variable for LCIG subjects who enter the 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 for shifts from baseline to lowest, highest and final 
value during the 12-week Treatment Period for each treatment group and overall subjects.
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


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
41
●
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
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 C.  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 12-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 Transition Period that meets the PCS criteria and is more extreme than their 
baseline value will be provided for LCIG subjects who enter the 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.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
42
10.4.1
Vital Sign and Weight Mean Changes
Analyses of mean change from baseline to each planned visit and to the minimum, 
maximum and final value during the 12-week Treatment Period will be presented by 
treatment group for each vital sign and weight variable.
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 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 baseline to each planned visit and to the minimum, 
maximum and final value during the Transition Period will be presented for each vital 
sign and weight variable for LCIG subjects who enter the 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 12-week 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 B.  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 12-week Treatment Period that meets the PCS criteria and is more extreme than their 
baseline value will be provided.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
43
A summary of the number and percentage of subjects who have at least one observation 
during the Transition Period that meets the PCS criteria and is more extreme than their 
baseline value will be provided for LCIG subjects who enter the 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 12-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, 
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.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
44
10.5.2
Potentially Clinically Significant (PCS) ECG Values
Criteria for PCS values have been predefined for selected ECG variables as outlined in 
Appendix D.  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 12-week 
Treatment Period that meets the PCS criteria and is more extreme than their baseline 
value will be provided.  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 
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 12-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.
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, 


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
45
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
●
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 12-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 Transition Period will 
also be provided for LCIG subjects who enter the Transition Period.
A listing will also be prepared that includes all subjects with 1 or more positive screens 
for any of the MIDI modules.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
46
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 
group with one or more affirmative responses to each of the 5 suicidal ideation questions, 
each of the 6 suicidal behavior questions, any of the 5 suicidal ideation questions, any of 
the 6 suicidal behavior questions, any suicidal ideation or behavior question, and the non-
suicidal self-injurious behavior question during the 12-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 Transition Period will also be provided 
for LCIG subjects who enter the 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 1).


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
47
13.0
Appendices


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
48
Appendix A.
Study Activities
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 
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
Xf
Concomitant Medication 
(including anti-PD and 
Dyskinesia medications)
X
X
X
X
X
X
X
X
X
X
X
Anti-PD Medication 
History
X
Physical Examinationg
X
X
X
X
X
X
X
X
X
Neurological Exam
X
X
X
X
X
X
X
X
Dermatological Examg
X
X
GI Examg
X
X
NJ or PEG-J decision 
X
Nasojejunal Tube 
Placement/Titrationh
(Optional)
X
PEG-J Placement 
Procedureh
X


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
49
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 
FUa
Transition to 
Commercial 
Visitsb
Radiological Check of 
Tube Placementi
X
PEG-J Site (Stoma) 
Check
Xj
X
X
Vital Signs/Weight
X
X
X
X
X
X
X
X
X
X
Height
X
ECG
X
X
X
Clinical Labs 
Xk
Xk
X
X
Urine Drug/Alcohol 
Screen
X
Special Laboratory Testsl
X
X
X
X
X
Pregnancy Testm
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
Dose Titration Diaryn
X
X
Subject Dosing Diary 
Completiono
X
X
X
X
X
PD Diary training and 
concordance evaluation
X
PD Diaryo
X
X
X
X
X


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
50
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6 
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 
FUa
Transition to 
Commercial 
Visitsb
LCIG System and Pump 
Training (Subject and 
Caregiver)
X
X
LCIG Titrationp
X
X
Study Drug Prescription 
Record (LCIG treatment 
group only)
X
X
X
X
X
X
X
Removal of PEG-Ja
X
LCIG Cassettes 
Dispensed
X
X
X
X
X
X
X
LCIG Cassettes Returned
X
X
X
X
X
X
MMSE 
X
Sleep Attacks 
Questionnaireq
X
X
X
X
X
X
X
X
C-SSRSr
X
X
X
X
X
X
X
X
X
X
MIDI 
X
X
X
X
X
X
X
X
X
UDysRSs
X
X
X
X
X
UPDRS II and IIIt
X
X
X
X
X
X
mAIMSu
X
X
X
X
X
PDQ-8
X
X
X
CGI-C 
X
X
X
X


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
51
OMT/LCIG
LCIG Treatment
OMT/LCIG Treatment
LCIG Treatment
Activity
V1 
Screening
V2 
Screening
V3 
Randomization
V4 NJ/PEG-J 
Placement D1
Titration 
Visits
V5 
Wk 
2
V6
Wk 
4
V7 
Wk 
8
V8 
Wk 12/ET
V9
Wk 13 
FUa
Transition to 
Commercial 
Visitsb
CGI-S
X
King's PD Pain Scale
X
X
X
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.
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 dyskinesia.
d.
Visit 4 for LCIG Treatment (LCIG) group only.
e.
Study-related assessments, procedures or activities cannot occur prior to subject completing signed informed consent process.  
f.
Update Medical/Neurological/PD History with any findings from Labs, Dermatologists, etc.
g.
At Screening Visit 1 and Randomization Visit 3 a full physical examination will be performed.  Symptom-driven physical examinations will be performed at subsequent 
visits.  Prior to Visit 3, 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 3 and Week 12/ET visit.  If a suspicious lesion is present, a biopsy should be 
obtained for proper diagnosis and confirmation that lesion does not meet exclusion criteria before the subject is randomized.
h.
For subjects randomized to LCIG treatment, 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, surgeon or interventional radiologist.  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.
i.
LCIG treatment 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.  Additional checks can be done at any time during treatment if indicated for worsening of Parkinsonian symptoms not responsive to extra doses.
j.
PEG-J site, stoma check will be done within 24 hours of PEG-J placement and anytime from Day 2 to 7 post PEG-J.
k.
PT/PTT will be performed only at Screening Visit 1.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
52
l.
Special labs to detect vitamin deficiencies, listed in Table 5 in the protocol, will be performed at the times indicated in the Appendix A, Study Activities.  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.
m.
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.
n.
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.
o.
The Subject Dosing Diary and the Parkinson's Disease Diary will be completed by the subjects or their caregivers for the 3 consecutive days prior to each visit.
p.
It is up to the discretion of the Investigator to determine how many titration days are necessary to obtain optimal clinical response.
q.
The Sleep Attacks Questionnaire will be used to screen for sleep attacks.  Results should be recorded in source but will not be entered in the clinical database.
r.
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.
s.
The subject's expected time of peak dose dyskinesia should be determined during screening and the UDysRS should be administered at this time throughout the study.
t.
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 Part III will only be done during Screening; all other UPDRS assessments will 
be done during "On" time.
u.
The mAIMS should be completed following the UDysRS at the subject's expected time of peak dose dyskinesia.
Note:
All applicable clinical, safety, health outcome and cognition assessments will be administered only by individuals qualified by the Sponsor.


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
53
Appendix B.
Potentially Clinically Significant Laboratory Values
Clinical Laboratory Tests
Very Low (VL)
Very High (VH)
Hematology
Activated partial thromboplastin 
time 
NA
> ULN
Hemoglobin
< 100 g/L (6.2 mmol/L)
> 40 g/L above ULN
Prothrombin Intl. Normalized 
Ratio
NA
> ULN
Leukocytes
< 2 × 109/L
> 100 × 109/L
Lymphocyte 
< 0.5 × 109/L
> 20 × 109/L
Neutrophil 
< 1× 109/L
NA
Platelets 
< 75× 109/L
NA
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)
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)
Urate
NA
> 590 umol/L (10 mg/dL)
Albumin
< 20 g/L
NA
Sodium
< 130 mmol/L
> 155 mmol/L
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
NA = not applicable; ULN = upper limit of normal
Adapted from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published:  May 28, 2009 
(v4.03:  June 14, 2010).


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
54
Appendix C.
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


Levodopa-Carbidopa Intestinal Gel (LCIG)
M15-535 – Statistical Analysis Plan
Version 1.0 – 21 May 2018
55
Appendix D.
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