COSMOS - COmedication Study Assessing Mono- and cOmbination Therapy With Levodopa-carbidopa inteStinal Gel
Conditions: Parkinson's Disease (PD)
Sponsor: AbbVie

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Title Page
Title
COSMOS - COmedication Study assessing Mono- and cOmbination 
therapy with levodopa-carbidopa inteStinal gel
(P16-831)
Protocol Version Identifier
Original Protocol
Date of Last Version of 
Protocol
14th June 2017
EU PAS Register Number
Study not registered
Active Substance
Not applicable
Medicinal Product
Not applicable
Product Reference
Not applicable
Procedure Number
Not applicable
Marketing Authorisation 
Holder(s)
EU
AbbVie Ltd. 
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
Joint PASS
Not applicable
Research Question and 
Objectives
The primary objective of this multi-country, retrospective and cross-
sectional, post-marketing observational study (PMOS) is to evaluate
the percentages of Advanced PD patients on LCIG monotherapy right 
after LCIG initiation and at 3, 6, 9, and 12 months, respectively.
The secondary objectives are
x
To describe PD medication management, and the main 
reasons justifying their use, directly prior to LCIG initiation, 
at LCIG initiation and during long-term LCIG treatment 
x
To describe LCIG infusion settings and substantial dose 
adjustments (section 9.2.7.7) and the respective reasons 
x
To describe the Healthcare Resource Utilization (HCRU) 
x
To identify the physician’s and patient’s/caregiver’s overall 
preference for the pharmacological treatment approach using
LCIG as monotherapy (section 9.2.7.7) vs. LCIG plus add-on 
PD medication
x
To identify predictors for achieving long-term monotherapy
(section 9.2.7.7) with LCIG vs. LCIG plus add-on PD 
medication, based on the patient’s profile and the physician’s 
profile
Version 1.0   14th June 2017
1
NCT03362879

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
To describe the latency from LCIG initiation until LCIG is 
given as a monotherapy and the average duration of LCIG 
monotherapy.
x
To describe the latency from the initiation of LCIG therapy 
until the introduction or tapering of each PD medication, or 
until substantial dose adjustments of LCIG
x
To investigate all of the above objectives for the participating 
countries who have enrolled a minimum of 20 study subjects 
Country(-ies) of Study
Approximately 15 countries in Europe (Austria, Bulgaria, Croatia, 
Romania, Czech Republic, Estonia, Hungary, Ireland, Germany, 
Netherlands, Slovakia and Spain), Canada and Australia, among 
others; final list of participating countries to be confirmed
Author
GMA and ad hoc functions
This study will be conducted in compliance with this protocol.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Version 1.0   14th June 2017
2

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Marketing Authorisation Holder(s)
Marketing Authorisation Holder(s)
EU
AbbVie Ltd. 
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
MAH Contact Person
Not applicable
Version 1.0   14th June 2017
3

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
1.0
Table of Contents
1.0 
Table of Contents.....................................................................4 
2.0 
Abbreviations...........................................................................7 
3.0 
Responsible Parties..................................................................8 
4.0 
Abstract ....................................................................................9 
5.0 
Amendments and Updates....................................................14 
6.0 
Milestones...............................................................................14 
7.0 
Rationale and Background...................................................14 
8.0 
Research Question and Objectives ......................................22 
9.0 
Research Methods .................................................................23 
9.1 
Study Design............................................................................................23 
9.2 
Setting ......................................................................................................25 
9.2.1 
Number of patients to be enrolled............................................................25 
9.2.2 
Site Selection Criteria ..............................................................................25 
9.2.3 
PMOS Duration .......................................................................................25 
9.2.4 
Inclusion Criteria .....................................................................................26 
9.2.5 
Exclusion Criteria ....................................................................................27 
9.2.6 
PMOS conduct.........................................................................................27 
9.2.7 
PMOS Procedures....................................................................................27 
9.2.7.1 
Center characterization ............................................................................28 
9.2.7.2 
Physician’s profile ...................................................................................28 
9.2.7.3 
Patient Demographics and socio-demographics ......................................28 
9.2.7.4 
Medical History and PD History..............................................................28 
9.2.7.5 
Previous PD medication and add-on PD treatment during LCIG 
Treatment .................................................................................................29 
9.2.7.6 
Concomitant Disease and Medication......................................................29 
9.2.7.7 
LCIG Treatment.......................................................................................30 
9.2.7.8 
Current APD Status at study visit ............................................................30 
9.2.7.9 
Healthcare Resource Utilization ..............................................................31 
9.2.7.10 
Quality of Life..........................................................................................31 
9.3 
Variables ..................................................................................................33 
9.3.1 
Safety Variables.......................................................................................33 
Version 1.0   14th June 2017
4

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.3.2 
Clinical variables .....................................................................................33 
9.4 
Data Sources ............................................................................................34 
9.4.1 
Source documents ....................................................................................34 
9.4.2 
Product supply .........................................................................................35 
9.4.3 
Health Outcomes......................................................................................35 
9.4.3.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) ..............................35 
9.4.3.2 
Non-Motor Symptoms Scale (NMSS).....................................................36 
9.4.3.3 
Parkinson’s Disease Questionnaire (PDQ-8)...........................................36 
9.4.3.4 
Parkinson’s Disease Sleep Scale-2 (PDSS-2)..........................................37 
9.4.3.5 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
disease- Rating Scale (QUIP-RS) ............................................................38 
9.4.3.6 
Healthcare Resource Utilization (HCRU) ...............................................38 
9.4.3.7 
Mini-Mental State Examination (MMSE) ...............................................38 
9.5 
Study Size ................................................................................................39 
9.6 
Data Management ....................................................................................39 
9.7 
Data Analysis...........................................................................................40 
9.8 
Quality Control ........................................................................................41 
9.9 
Limitations of the Research Methods ......................................................42 
9.10 
Other Aspects...........................................................................................42 
10.0 
Protection of Human Subjects..............................................42 
11.0 
Management and Reporting of Complaints........................43 
11.1 
Medical Complaints.................................................................................43 
11.1.1 
Adverse Event Definition and Serious Adverse Event Categories..........43 
11.1.2 
Severity ....................................................................................................45 
11.1.3 
Relationship to Pharmaceutical Product ..................................................45 
11.1.4 
Serious Adverse Event Collection Period................................................45 
11.1.5 
Serious Adverse Event Reporting............................................................46 
11.1.5.1 
Safety Reporting in the Retrospective section of the study.....................46 
11.1.6 
Pregnancy Reporting................................................................................47 
12.0 
Product Complaint................................................................47 
12.1.1 
Definition .................................................................................................47 
12.1.2 
Reporting..................................................................................................48 
Version 1.0   14th June 2017
5

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
13.0 
Plans for Disseminating and Communicating Study 
Results.....................................................................................48 
14.0 
References...............................................................................50 
15.0 
Affiliate Agreement page ......................................................55 
Annex 15. 
Patient Questionnaires..........................................................57 
A. 
Parkinson’s Disease Quality of Life Questionnaire 
(PDQ-8)...................................................................................57 
B. 
Questionnaire for Impulsive-Compulsive Disorders 
in Parkinson's Disease - Rating Scale (QUIP-RS)..............58 
C. 
Parkinson's Disease Sleep Scale-2 (PDSS-2).......................59 
D. 
Beliefs Medication Questionnaire (18-item BMQ).............61 
Annex 16.  
Physician Questionnaires......................................................63 
A. 
Unified Parkinson's Disease Rating Scale (UPDRS)..........63 
B. 
Non-Motor Symptoms Scale for Parkinson’s Disease 
(NMSS) ...................................................................................69 
C. 
Mini-Mental State Examination (MMSE) ..........................70 
Annex 17. 
Study Protocol Signature page.............................................73 
Version 1.0   14th June 2017
6

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
2.0
Abbreviations
ADL
Activities of Daily Living
AE 
Adverse Event
APD
Advanced Parkinson’s disease
AUDD
Authorization for Use and Disclosure of Data
BMQ
DBS
Beliefs medication questionnaire
Deep Brain Stimulation
CDD
Continuous Drug Delivery
CRA
Clinical Research Associate
CRO
CSAI
Clinical Research Organization
Continuous sub-cutaneous apomorphine infusion
eCRF
Electronic Case Report Form
HCRU
Healthcare Resource Utilization
ICF
Informed Consent Form
IRB
Institutional Review Board
LCIG
Levodopa-Carbidopa Intestinal Gel
LD
Levodopa
LEDD
Levodopa equivalent daily dosage
MD
Doctor of Medicine
MedDRA
MMSE
Medical Dictionary for Regulatory Activities
Mini-Metal State Examination 
NMSS
Non-Motor Symptom Scale
PD
Parkinson’s disease
PDQ-8
Parkinson’s Disease Questionnaire-8
PDSS-2
Parkinson’s Disease Sleep Scale-2
PEG-J
Percutaneous endoscopic gastrostomy- with jejunal extension
PC
Product Complaint
PLMS
Periodic Limb Movements of Sleep
PRO
Patient reported outcomes
QUIP-RS
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating 
Scale
REM
Rapid Eye Movement
RLS
Restless Legs Syndrome
SAE
Serious Adverse Event
Version 1.0   14th June 2017
7

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
4.0
Abstract
Title: COSMOS - COmedication Study assessing Mono- and cOmbination therapy with levodopa 
carbidopa inteStinal gel
Rationale and Background: Parkinson's disease (PD) is a chronic and progressive neurodegenerative 
disorder with a worldwide estimated prevalence of 0.3% in the general population 40 years of age and 
older [1]. The most effective symptomatic therapy for PD remains levodopa, a precursor of dopamine. 
However, within several years of levodopa therapy initiation, a considerable number of patients develop 
complications, and after 5 to 10 years of treatment at least 50% of patients develop motor fluctuations 
and abnormal involuntary movements (dyskinesia).
As PD progresses, even complex oral drug regimens may become insufficient for symptom control [2].
Therefore, other therapeutic strategies have been developed, including treatments based on continuous 
drug delivery (CDD) [3-5].
Among the enteric CDD formulations, levodopa-carbidopa intestinal gel (LCIG) is the only formulation 
of levodopa and carbidopa which has been found to be suitable for continuous long-term intestinal 
infusion so far.
LCIG (Duodopa®) appears to possess the potential to be used as monotherapy in many patients, or at 
least enable significant reductions of the add-on PD medication. Thereby, LCIG may achieve a much-
needed simplification of the treatment regimen, allowing for a reduction of detrimental drug-drug 
interactions (DDI) [6].
So far, data on patients in whom LCIG monotherapy or significant reductions of add-on PD medication 
was achieved, have been derived from two clinical studies with rigorous protocols [7, 8], and therefore 
cannot be easily translated into routine clinical practice. Also, recent observational studies demonstrated 
overall varying approaches in the management of add-on PD medications in routine clinical practice 
before and after initiation of LCIG treatment [9, 10].
In a multinational registry on the efficacy and safety of LCIG in routine care (GLORIA registry), 36-
40% of APD patients were treated over 24 months with LCIG monotherapy (without any additional oral 
PD medication); however no background information on the rationale for the use of add-on PD 
medication (e.g., introduction/tapering/maintenance) was collected [11].
In summary, no systematic, comprehensive and homogeneous real-world data are available – neither on 
LCIG monotherapy or LCIG in combination with add-on PD medication, nor on the management of add-
on PD medications before or upon LCIG initiation, or during long-term LCIG maintenance therapy.
The present study attempts to fill this knowledge gap and generate relevant data from routine clinical 
practice on the usability of LCIG as a monotherapy and in combination with add-on PD medications. In 
addition, useful data on the handling of add-on PD medication (e.g. tapering, introduction) upon LCIG 
initiation and over long-term use shall be collected.
Research Question and Objectives: The primary objective of this multi-country, retrospective and 
cross-sectional, post-marketing observational study (PMOS) is to evaluate the percentages of Advanced 
PD patients on LCIG monotherapy right after LCIG initiation and at 3, 6, 9, and 12 months,
respectively.
The secondary objectives are
x
To describe PD medication management, and the main reasons justifying their use, directly 
prior to LCIG initiation, at LCIG initiation and during long-term LCIG treatment 
Version 1.0   14th June 2017
9

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
To describe LCIG infusion settings and substantial dose adjustments and the respective reasons 
x
To describe the Healthcare Resource Utilization (HCRU) 
x
To identify the physician’s and patient’s/caregiver’s overall preference for the pharmacological 
treatment approach using LCIG as monotherapy vs. LCIG plus add-on PD medication
x
To identify predictors for achieving long-term monotherapy with LCIG vs. LCIG plus add-on 
PD medication, based on the patient’s profile and the physician’s profile
x
To describe the latency from LCIG initiation until LCIG is given as a monotherapy and the 
average duration of LCIG monotherapy.
x
To describe the latency from the initiation of LCIG therapy until the introduction or tapering of 
each PD medication, or until substantial dose adjustments of LCIG
x
To evaluate the percentage of patients who are on LCIG monotherapy, PD medication 
management and HCRU for the participating countries who have enrolled  a minimum of 20 
study subjects 
Study Design: This is a multi-country, retrospective and cross-sectional, post-marketing observational 
study (PMOS) of patients with APD treated with LCIG in a routine clinical setting. Patients who are 
receiving LCIG according to the approved local product label and reimbursement guidelines will be 
asked to participate.
This study will include a retrospective section, collecting the below specified data from patient’s medical 
records from the time of the decision to start LCIG treatment until the present day, and a single study 
visit (cross-sectional) with clinical status and subjective assessments of patients at present time.
Patients, who have received LCIG for at least 12 months, and who satisfy all the inclusion criteria and 
exclusion criteria will be eligible to be enrolled into this PMOS. All eligible LCIG patients will be 
included consecutively at each participating study site.
The primary endpoint of this PMOS will be the percentages of APD patients on LCIG monotherapy right 
after LCIG initiation (after permanent system placement) and at 3, 6, 9, and 12, respectively.
The secondary endpoints are:
x
Descriptive data from patient’s PD medication:
x
For add-on PD medication: percentage of patient on each PD medication (by drugs 
and class), total daily dose and levodopa equivalent Daily dose (LEDD) , posology 
(number of times per day);
x
For LCIG infusion settings and substantial dose adjustments: total dose per day and 
specific for each type of dose (morning dose and continuous dose) and number of 
hours of infusion.
x
Tapering process: number of days required for the tapering process, total dose per 
day and posology for add-on PD medication prior to LCIG initiation, at LCIG 
initiation (titration) or during ongoing LCIG treatment
x
Main reasons for introduction or tapering of add-on PD medication or LCIG 
substantial dose adjustments 
x
Latency and duration of treatments data:
x
Number of days or months from LCIG initiation until LCIG is given as a 
monotherapy and the duration of LCIG monotherapy.
x
Number of days or months from LCIG initiation until the introduction or tapering of 
each PD medication, or until any LCIG substantial dose adjustments.
Version 1.0   14th June 2017
10

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
LCIG monotherapy vs LCIG plus add-on PD medication data:
x
Healthcare Resource Utilization, as measured by Healthcare Resource Utilization 
Questionnaire (HCRU)
x
Patient’s, caregiver’s, and physician’s overall preference on LCIG monotherapy vs. 
LCIG plus add-on PD medication, percentage of patient’s and physician’s 
preference for each of the options
x
Predictors for LCIG as monotherapy vs. LCIG plus add-on PD medication based on 
the patient’s profile, including socio-demographics , clinical status (motor and non-
motor symptoms), Levodopa-equivalent dose (LED), PD medication and Quality of 
Life
x
Predictors for LCIG as monotherapy vs. LCIG plus add-on PD medications based 
on the physician’s profile including experience as measured by, number of years on 
APD patient management, number of years using LCIG therapy, and number of 
patients on LCIG therapy
Population: Patients that may be enrolled in this study are adult patients with APD, who are under 
treatment with LCIG according to the local product label and specific reimbursement criteria. Decision 
to offer study participation has been made by their physician, based on meeting all of the inclusion 
criteria and none of the exclusion criteria. 
A total of approximately 400 patients with APD will be included.
Patients must meet all of the following criteria: 
1.
Patients diagnosed with APD and on LCIG treatment for at least 12 months 
2.
Patients must have been on continuous LCIG treatment for at least 80% of days in the 
preceding year
3.
Patients must be treated by the same physician (PI or co-investigator) since the initiation of 
LCIG.
4.
Decision to treat with LCIG was made and therapy was started by the physician prior to any 
decision to approach the patient to participate in this study
5.
Prior to any data collection, the patient, or legal authorized representative (LAR) has voluntarily 
signed an Authorization for Use/Disclosure of Data (AUDD)/informed consent form (ICF) 
according to national regulations after the study has been explained and the subject has had the 
opportunity to have questions answered
Patients must not be enrolled if they meet any of the following criteria: 
1.
Participation in a concurrent or a previous interventional clinical trial during which the patient 
was on LCIG therapy
2.
Lack of motivation or insufficient language skills to complete the study questionnaires.
Variables: This is a PMOS with the objective of collecting data on the clinical practice of LCIG 
treatment upon treatment initiation and long-term follow-up.
Clinical Variables:
Information about the previous PD medication, and add-on PD medication and LCIG infusion settings 
will be retrospectively collected from patient`s medical records.
Actual Parkinson's disease status and motor symptoms/motor complications will be measured using the 
following tools:
Version 1.0   14th June 2017
11

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
Duration of OFF time and dyskinesia (hours during the day prior to the clinical visit) as
reported by the patient
x
UPDRS Parts III (motor evaluation) and IV (Treatment complication)
The following health outcomes will be measured using the following tools:
x
UPDRS Part I (evaluation of mentation, behavior, and mood)
x
UPDRS Part II (self-evaluation of the activities of daily living (ADLs))
x
UPDRS Part V (Modified Hoehn and Yahr stage of severity of Parkinson's disease)
x
PDQ-8 (Parkinson Disease Questionnaire) to evaluate PD patient’s quality of life.
Non-motor symptoms including specific tool for sleep/daytime sleepiness, impulse control disorders and 
mental status will be measured using the following tools:
x
Non-motor Symptoms Scale (NMSS)
x
Parkinson´s Disease Sleep Scale-2 (PDSS-2)
x
Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease- Rating 
Scale (QUIP-RS)
x
Mini-Mental state Examination (MMSE)
Healthcare utilization resources and patient’s beliefs on medication will be measured using the 
following tools:
x
HCRU (Healthcare resource utilization questionnaire)
x
Beliefs Medication questionnaire (BMQ)
Safety Variables:
The physician will be asked to report Serious Adverse Events (SAEs), Product Complaints (PCs), and 
pregnancies.
Data Sources: Source documents are defined as original documents, data and records. These may 
include hospital records, clinical and office charts, laboratory data/information, pharmacy dispensing and 
other records, recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media and/or x-radiographs. Data collected during this PMOS must be recorded 
on the appropriate source documents. The only exception will be for patient/caregiver-completed 
questionnaires. There will be no corresponding source documentation for the latter, because the 
patient/caregiver completes the forms directly on the paper questionnaire (that is, these questionnaires 
are the source data). Patient/caregiver self-administered questionnaires will be completed on paper forms 
and then submitted to the designated CRO for data entry into the eCRF system. 
The PMOS physician/institution will permit PMOS-related monitoring, audits, Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) review, and regulatory inspection(s), providing 
direct access to source documents. 
Study Size: The sample size of approximately 400 patients has been determined based on the rationale 
of the study.
Sample size calculation was based on pre-defined precision of the estimators of the primary endpoints,
expressed as the maximum length of the corresponding two-sided 95% confidence intervals. In order to 
achieve a precision of ± 5% (i.e. the confidence intervals are not wider than 10%), at least 385 
(evaluable) patients are necessary. 
In this observational retrospective and cross-sectional study, only a small number of non-evaluable 
patients are expected. Therefore, it is planned to include a total number of approximately 400 patients.
Version 1.0   14th June 2017
12

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Data Analysis:
All data assessed will be analyzed using descriptive statistics. All statistical analyses will be carried out 
by means of the SAS® package (version 9.4 or higher).
Two-sided 95% confidence intervals will be provided for primary and secondary endpoints defined by 
proportions. Confidence intervals will also be calculated for differences between pre-defined groups of 
patients, if appropriate (e.g. LCIG monotherapy vs. LCIG plus add-on PD medication).
Logistic regression and subgroup analyses will be applied to investigate the impact of potential 
prognostic factors on the primary endpoints and to identify predictors for LCIG monotherapy.
Milestones: Enrollment will be completed within approximately 12 months. 
Planned start date (FPI) 15th Dec 2017
Planned end date (LPO) 15th Dec 2018
Final Report of Study Results (CSR) 15th November 2019
Version 1.0   14th June 2017
13

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
5.0
Amendments and Updates
Not applicable
6.0
Milestones
Major study milestones and their planned dates are as follows:
Start of Data Collection (FPI):
15th December 2017
End of Data Collection (LPO):
15th December 2018
Study Progress Report X:
Not applicable
Interim Report X:
Not applicable
Registration in the EU PAS register
Not applicable
Final Report of Study Results:
15th November 2019
7.0
Rationale and Background
Parkinson’s disease (PD)
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a 
worldwide estimated prevalence of 0.3% in the general population 40 years of age and 
older [1]. As incidence and prevalence rise with age, more than 1% of the population over 
the age of 65 is afflicted with PD [12-14]. The mortality for elderly PD patients is two to 
five times higher than in age-matched controls [15]. PD is caused by idiopathic 
degeneration of dopamine-producing cells in the substantia nigra of the midbrain [16].
The resulting dopamine depletion disrupts connections to the motor cortex and the 
thalamus, leading to the clinical cardinal signs of PD: resting tremor, cogwheel rigidity 
and bradykinesia, along with postural instability [17]. Additional diagnostic criteria are 
asymmetrical onset of symptoms and symptomatic response to levodopa (LD) [17, 18].
Due to PD’s distinctive clinical signs and for the lack of confirming diagnostic tests, 
diagnosis is generally based on the clinical picture and supported by the observation of a 
clinical improvement upon dopaminergic drug therapy [19-21].
Version 1.0   14th June 2017
14

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
The most effective symptomatic therapy for PD remains levodopa (LD), a precursor of 
dopamine. LD is usually administered together with carbidopa, a decarboxylase-inhibitor 
that improves the bioavailability of levodopa in the central nervous system. However, 
within several years of levodopa therapy initiation, a considerable number of patients 
develop complications, and after 5 to 10 years of treatment at least 50% of patients 
develop motor fluctuations and abnormal involuntary movements (dyskinesia) [22].
Possible causes for those detrimental LD effects include the sensitization of postsynaptic 
receptors after oral, pulsatile stimulation, and also the progressive degeneration of the 
nigrostriatal dopamine terminals that take up exogenously administered LD and convert it 
to dopamine for subsequent storage and release [2, 22-24]. In consequence, patients in the 
advanced stages of the disease experience an enhanced sensitivity to small changes in 
plasma LD levels, which narrows the therapeutic window and negatively impacts motor 
function [25, 26]. As there is no gastric absorption of LD, gastric emptying and transit via 
the pyloric sphincter are critical factors for regular intestinal LD absorption [27].
Gastrointestinal dysfunction with erratic gastric emptying, a symptom many patients 
develop over the years, impairs intestinal absorption and is another common cause of poor 
effectiveness of LD in PD. 
Motor fluctuations with alternating periods of good and poor symptom control and 
dyskinesias are a common sign for the progression to the advanced disease stages. In 
patients with advanced PD (APD), treatment regimens have become complex over the 
years. Upon the occurrence of complications, initial treatment strategies are based on 
optimization of oral LD therapy, and may include minimizing oral doses and shortening 
the dosing intervals. Besides LD, a variety of PD drugs (including dopamine agonists, 
monoamine oxidase [MAO] B inhibitors, anticholinergic agents, amantadine, catechol-o-
methyl transferase [COMT] inhibitors) are available for symptomatic treatment, which 
may be employed as monotherapy or in combination. However, complex oral drug 
regimens are particularly burdensome to APD patients, as patients are exposed to 
Version 1.0   14th June 2017
15

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
increased risks related to swallowing problems and choking (due to dysphagia), and drug-
drug interactions. Moreover, patient adherence to complex oral treatment regimens is 
often strongly impaired due to progressive cognitive deficits. 
As progressive deterioration of the nigrostriatal dopaminergic transmission occurs, even 
complex oral drug regimens may become insufficient for symptom control [2]. Therefore, 
other therapeutic strategies have been developed, including treatments based on 
continuous drug delivery (CDD) [3-5], such as continuous subcutaneous apomorphine 
infusion therapy (CSAI), or levodopa-carbidopa intestinal gel (LCIG), or even surgical 
interventions such as implantation of deep brain stimulation (DBS) devices. However, in 
treatment options such as CSAI and DBS, continued use of PD medication appears to 
remain necessary for many APD patients. In many cases, CSAI does allow for withdrawal 
or tapering of other PD treatments such as COMT-inhibitors, dopamine agonists, and 
MAO-B inhibitors, as well as reductions of levodopa dosages. Still, CSAI is only rarely 
used as monotherapy as this is often limited by poor tolerability of high doses of 
apomorphine [28-32]. Studies on DBS treatment show that, even though DBS may enable 
reductions in the dosing of PD medication by 35-60%, patients can very rarely be 
managed without any additional therapy [28, 33, 34].
Levodopa-Carbidopa Intestinal Gel (LCIG)
Various levodopa CDD formulations (intravenous and enteral) have been under 
investigation for already more than 30 years [35-37]. Among the enteric CDD 
formulations, levodopa-carbidopa intestinal gel (LCIG) is the only formulation of LD and 
carbidopa which has been found to be suitable for continuous long-term intestinal infusion 
so far [38]. The LCIG system has been on the market for over 10 years, and is currently 
approved in more than 40 countries in the treatment of levodopa-responsive APD. In the 
Version 1.0   14th June 2017
16

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
majority of countries, it is marketed by AbbVie (AbbVie Ltd, United Kingdom) under the 
trade names Duodopa® and Duopa® (in the United States).
The LCIG suspension is provided in 100 mL cassettes to be connected to an ambulatory 
pump (CADD-Legacy® 1400 portable pump) that delivers the cassette content directly 
into the duodenum. The LCIG infusion rate is programmable and can be adjusted in steps 
of 0.1 mL/h (equivalent to 2 mg levodopa/h). In addition, patients can self-administer 
extra doses during the day by pressing a dose button to infuse a pre-programmed bolus 
(usually 10 to 20 mg per bolus). Patients may also (if instructed to do so by their treating 
physician) adjust the amount of the extra dose according to their needs. 
During an optional test phase with application of LCIG via a nasojejunal (NJ) tube, the 
treatment response and tolerability of LCIG may be assessed before proceeding to the 
surgical procedure to permanently place a tube into the small bowel. The percutaneous 
endoscopic gastrostomy with a jejunum tube placement (PEG-J) is a common procedure 
and typically does not require general anesthesia (mostly conscious sedation) [39].
Although the percutaneous endoscopic gastrostomy (PEG) procedure is relatively safe and 
major complications are rare, device- and procedure-related undesirable effects may 
occur. Drug-related undesirable effects that occur frequently with the Duodopa system 
include nausea and dyskinesia. Device- and procedure related undesirable effects include 
abdominal pain, complications of device insertion, excessive granulation tissue, incision 
site erythema, postoperative wound infection, post procedural discharge, procedural pain 
and procedural site reaction. Less common complications of the PEG procedure observed 
with the LCIG system include bezoar, ileus, implant site erosion/ulcer, intestinal 
hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, 
intussusception, pancreatitis, peritonitis, pneumoperitoneum and post-operative wound 
infection [40]. These complications may result in serious events which might impose a 
need for further surgery, or may be even fatal. 
Version 1.0   14th June 2017
17

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
LCIG Clinical Data
LCIG efficacy and safety in patients has been corroborated in many clinical trials in 
patients with APD [4, 41-44]. Outcomes from a randomized, double-blind, controlled, 
multi-country study over 12 weeks in 71 patients comparing LCIG and oral 
levodopa/carbidopa as adjunct therapy to optimized oral treatment have been published 
[7]. In LCIG patients, a significant reduction in off- time versus baseline and versus oral 
levodopa/carbidopa as well as an increase in on-time without dyskinesias versus oral 
levodopa/carbidopa were observed.
A subsequent open-label extension study showed sustained efficacy in patients continuing 
LCIG therapy [45]. The LCIG-naïve patients, i.e. those previously randomized to oral 
levodopa/carbidopa in the double-blind phase, showed a similar efficacy with regard to 
off- and on-time without dyskinesias as the patients randomized to LCIG. 
A multi-national study focusing primarily on tolerability and safety enrolled 354 patients 
with APD who were observed over 54 weeks in an open-label design including a 
nasojejunal test phase [8, 46]. In this study, 76.8% of patients completed the study, while 
7.6% of patients withdrew due to AEs. The efficacy findings confirmed the data of the 
above described double-dummy study [7] showing similar reductions in daily off-time 
and increases in on-time without dyskinesias over 1 year, and also showed sustained 
effects under stable levodopa doses.
In addition, interim data from an ongoing post-marketing observational study on the use 
of LCIG in routine care conditions showed sustained improvements in off-time and on-
time with dyskinesias, as well as improvements in Unified Parkinson’s Disease Rating 
Scale (UPDRS) II and III scores during on-time. According to the 12-month interim 
outcomes of the first 172 included patients, the mean LCIG dose remained stable and the 
Version 1.0   14th June 2017
18

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
tolerability and safety data were consistent with the established safety profile of LCIG 
[10].
LCIG and add-on PD medication use
According to the label outside of the United States, LCIG should be initially used as a 
monotherapy [40]. In clinical practice however, a transitory titration period is usually 
needed during which all other oral or transdermal therapies are tapered. Many patients are 
expected to be treated sufficiently by LCIG daytime infusions. Some patients, however, 
may need additional therapy for the night time and eventually add-on combination therapy 
may be warranted, in order to increase bioavailability and effectiveness [47].
Data from the above mentioned clinical trials [7, 8, 46] also suggest that LCIG treatment 
can reduce the need for other PD medication.
In the pivotal clinical trial on LCIG [7], patients had to be receiving stable doses of oral 
levodopa for at least four weeks prior to enrollment. If receiving sustained release 
levodopa-carbidopa, levodopa-carbidopa-entacapone or other formulations of levodopa, 
they had to be converted to equivalent doses of levodopa-carbidopa immediate release 
(LC-IR) formulations and remain on stable doses for at least four weeks before 
enrollment. During the double-blind phase patients had to stay then on their prior PD 
medication (to ensure blinding). Upon entering the open-label extension study, when 
adjustment of concomitant PD medication was again permitted, these were discontinued 
in many patients on LCIG. A subanalysis showed that percentage of patients on add-on
PD medication dropped from 89% (n = 71) during the double-blind to 37% (n = 62) by 
day 1 of the extension study [6].
In the second, open-label clinical trial, 80% of patients were on add-on PD medications 
upon study start. As per study protocol, prior to LCIG initiation, tapering of add-on PD 
Version 1.0   14th June 2017
19

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
medication was required and limited to oral LD medication, after 4 first weeks of the 
study, the add-on PD medication could be reintroduce. By end of the study (week 54), 
77% of patients remains on LCIG monotherapy [6, 8].
Importantly, those two clinical trials differed, among other aspects, in the required 
tapering process: in one study, tapering was required prior to LCIG initiation [8, 46],
while in the other study, tapering was optional and the timing prior to or after LCIG 
initiation was not specified [7]. Comparing the results of both studies, the method of
tapering did not appear to have a clear impact on adverse events, specifically, no differing 
rates of dyskinesia or signs of dopamine withdrawal were observed [6]. In both clinical 
trials, certain add-on PD medications, including other levodopa preparations or 
apomorphine sub-cutaneous (SC), were not allowed, and data are thus not easily 
translatable to real-world practice. 
In a multinational registry on the efficacy and safety of LCIG in routine care (GLORIA 
registry), 36-40% of APD patients were treated over 24 months with LCIG monotherapy 
(without any additional oral PD medication); however no background information on the 
rationale for the use of add-on medication (e.g., introduction/tapering/maintenance) was 
collected [11].
Interim outcomes of the GREENFIELD observational study on 145 patients with APD in 
Italy compared clinical data before and during LCIG therapy. Initiation of LCIG led to 
significant clinical improvement and the intake of add-on PD medication was largely 
reduced: for instance, oral levodopa use decreased from 96.9% before LCIG start to 5% 
(during the day) and 26% (at night); use of dopamine agonists decreased from 64.1% to 
30%. However, thus far, results are only derived from a mean treatment period of 14 
months, and date are still incomplete [9].
Version 1.0   14th June 2017
20

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Rationale
LCIG (Duodopa®) appears to possess the potential to be used as monotherapy in many 
patients, or at least enable significant reductions of the add-on PD medication. Thereby, 
LCIG may achieve a much-needed simplification of the treatment regimen, allowing for a 
reduction of detrimental drug-drug interactions [6].
So far, data on patients in whom LCIG monotherapy or significant reductions of add-on
PD medication was achieved, have been derived from two clinical studies with rigorous 
protocols [7, 8], and therefore cannot be easily translated into routine clinical practice. 
Also, recent observational studies demonstrated overall varying approaches in the 
management of add-on PD medications in routine clinical practice before and after 
initiation of LCIG treatment [9, 10].
For APD patients under LCIG treatment there is an opportunity to substantially reduce the 
need for other add-on PD medication and/or completely discontinue them. This is the 
primary hypothesis that generates this study.
In summary, no systematic, comprehensive and homogeneous real-world data are 
available – neither on LCIG monotherapy or LCIG in combination with add-on PD 
medication, nor on the management (reasons for use and time course) of add-on PD 
medications before or upon LCIG initiation, or during long-term LCIG maintenance 
therapy. 
The present study attempts to fill this knowledge gap and generate relevant data from 
routine clinical practice on the usability of LCIG as a monotherapy and in combination 
with add-on PD medications. In addition, useful data on the handling of add-on PD 
medication (e.g., tapering, introduction), upon LCIG initiation and over long-term use 
shall be collected.
Version 1.0   14th June 2017
21

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
8.0
Research Question and Objectives
The primary objective of this multi-country, retrospective and cross-sectional, post-
marketing observational study (PMOS) is to evaluate the percentages of Advanced PD 
patients on LCIG monotherapy right after LCIG initiation and at  3, 6, 9, and 12 months, 
respectively. 
The secondary objectives are:
x
To describe PD medication management, and the main reasons justifying their use, 
directly prior to LCIG initiation, at LCIG initiation and during long-term LCIG 
treatment 
x
To describe LCIG infusion settings and substantial dose adjustments and the 
respective reasons 
x
To describe the Healthcare Resource Utilization (HCRU) 
x
To identify the physician’s and patient’s/caregiver’s overall preference for the 
pharmacological treatment approach using LCIG as monotherapy vs. LCIG plus 
add-on PD medication
x
To identify predictors for achieving long-term monotherapy with LCIG vs. LCIG 
plus add-on PD medication, based on the patient’s profile and the physician’s 
profile
x
To describe the latency from LCIG initiation until LCIG is given as a 
monotherapy and the average duration of LCIG monotherapy
x
To describe the latency from the initiation of LCIG therapy until the introduction 
or tapering of each PD medication, or until substantial dose adjustments of LCIG
x
To evaluate the percentage of patients who are on LCIG monotherapy, PD 
medication management and HCRU for the participating countries who have 
enrolled a minimum of 20 study subjects.
Version 1.0   14th June 2017
22

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.0
Research Methods
9.1
Study Design
This is a multi-country, retrospective and cross-sectional, post-marketing observational 
study (PMOS) of patients with APD treated with LCIG in a routine clinical setting. 
Patients who are receiving LCIG according to the approved local product label and 
reimbursement guidelines will be asked to participate. 
This study will include a retrospective section, collecting below specified data from 
patient’s medical records from the time of the decision to start LCIG treatment until the 
present day, and a single study visit (cross-sectional) with clinical status and subjective 
assessments of patients at present time.
Patients, who have received LCIG for at least 12 months, and who satisfy all the inclusion 
criteria and none of the exclusion criteria will be eligible to be enrolled into this PMOS. 
All eligible LCIG patients will be identified consecutively and offered the opportunity to 
participate in the study.
To assess the generalizability of the data from the patients enrolled, the physician will be 
asked to document on a separate Case Reporting Form the number of patients who are 
eligible but refuse to participate in the study. Only age ranges (<30 years, 30-45 years, 45-
65 and > 65 years) and reason(s) for not participating will be collected.
The primary endpoint of this PMOS will be the percentages of APD patients on LCIG 
monotherapy right after LCIG initiation and at 3, 6, 9, and 12, respectively. 
The secondary endpoints are:
x
Descriptive data from patient’s PD medication: 
x
For add-on PD medication: percentage of patient on each PD medication 
(by drugs and class), total daily dose and levodopa equivalent Daily dose 
(LEDD) , posology (number of times per day); 
x
For LCIG infusion settings and substantial dose adjustments: total dose 
per day and specific for each type of dose (morning dose and continuous 
dose) and number of hours of infusion.
Version 1.0   14th June 2017
23

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
Tapering process: number of days required for the tapering process, total 
dose per day and posology for  add-on PD medication prior to LCIG 
initiation, at LCIG initiation (titration) or during ongoing LCIG 
treatment
x
Main reasons for introduction or tapering of add-on PD medication or 
LCIG substantial dose adjustments 
x
Latency and duration of treatments data: 
x
Number of days or months from LCIG initiation until LCIG is given as a 
monotherapy and the duration of LCIG monotherapy.
x
Number of days or months from LCIG initiation until the introduction or 
tapering of each PD medication, or until any LCIG substantial dose 
adjustments. 
x
LCIG monotherapy vs LCIG plus add-on PD medication data:
x
Healthcare Resource Utilization, as measured by Healthcare Resource 
Utilization Questionnaire (HCRU)
x
Patient’s, caregiver’s, and physician’s overall preference on LCIG 
monotherapy vs. LCIG plus add-on PD medication, percentage of 
patient’s and physician’s preference for each of the options 
x
Predictors for LCIG as monotherapy vs. LCIG plus add-on PD 
medication based on the patient’s profile, including socio-demographics, 
clinical status (motor and non-motor symptoms), Levodopa-equivalent 
dose (LED), PD medication and Quality of Life
x
Predictors for LCIG as monotherapy vs. LCIG plus add-on PD 
medications based on the physician’s profile including experience as 
measured by number of years on APD patient management, number of 
years using LCIG therapy, and number of patients on LCIG therapy
Version 1.0   14th June 2017
24

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.2
Setting
9.2.1
Number of patients to be enrolled
Approximately 400 adult patients diagnosed with APD, on current treatment with LCIG, 
and treated with LCIG for at least 12 months prior to study inclusion, will be enrolled in 
approximately 15 countries in Europe (Austria, Bulgaria, Croatia, Romania, Czech 
Republic, Estonia, Hungary, Ireland, Germany, Netherlands, Slovakia and Spain), Canada 
and Australia, among others, the final list of participating countries to be confirmed. All 
eligible patients at a given site will be enrolled consecutively in order to minimize 
selection bias.
9.2.2
Site Selection Criteria
The participating sites will be hospitals or clinics experienced in treating patients with 
APD, and with experience in LCIG treatment. Sites must have the ability to appropriately 
conduct the PMOS in accordance with applicable legal and regulatory requirements.
Participating physicians should have been involved in the respective patient’s 
management since initiation of LCIG therapy.
9.2.3
PMOS Duration 
This PMOS consists of one single visit. The observational period is mainly retrospective 
and includes one cross-sectional study visit. Data gathered are derived from the time prior 
to initiation of LCIG therapy until the day of the study visit (see Figure 1).
Version 1.0   14th June 2017
25

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Figure 1: Study Schematic
9.2.4
Inclusion Criteria
1. Patients diagnosed with APD and on LCIG treatment for at least 12 months 
2. Patient must have been on continuous LCIG treatment for at least 80% of days in 
the preceding year
3. Patients must be treated by the same physician (PI or co-investigator) since the 
initiation of  LCIG treatment
4. Decision to treat with LCIG was made and therapy was started by the physician 
prior to any decision to approach the patient to participate in this study
5. Prior to any data collection, the patient, or legal authorized representative (LAR) 
has voluntarily signed an Authorization for Use/Disclosure of Data 
(AUDD)/informed consent form (ICF) according to national regulations after the 
study has been explained and the subject has had the opportunity to have questions 
answered
Version 1.0   14th June 2017
26

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.2.5
Exclusion Criteria
1. Participation in a concurrent or a previous interventional clinical trial during which 
the patient was on LCIG therapy
2. Lack of motivation or insufficient language skills to complete the study 
questionnaires
9.2.6
PMOS conduct
Physicians will be provided with study information including a protocol, AUDD/ICF 
template, paper-based patient questionnaires, and access to the electronic Case Report 
Forms (eCRFs).
The study visit will take place during a regular clinic visit as foreseen per routine clinical 
practice.
Clinical data associated with this PMOS will be collected electronically (eCRF) via a web 
based electronic data capture (EDC) system. Access to the EDC system is granted by 
logging in with username and password. Patient/caregiver self-administered 
questionnaires will be completed on paper forms and then entered into the database by the 
designated contract research organization (CRO) GKM Gesellschaft für 
Therapieforschung mbH, Munich, Germany.
9.2.7
PMOS Procedures
Data for this PMOS will be collected during one single patient visit in accordance with 
routine clinical practice as indicated in Table 1, Summary of Assessments.
Version 1.0   14th June 2017
27

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.2.7.1
Center characterization
The physician will provide information on the site, including institution type, origin of 
service, average number of PD and APD patients seen at site per year, number of 
physicians managing PD patients at site, support services/functions available at the site, 
access to device aid therapies treatments, and average yearly frequency of visits of PD and 
APD patients (on device-aided therapy).
9.2.7.2
Physician’s profile
The physician is requested to document his/her experience in the treatment of APD 
patients and in the use of LCIG, including therapeutic specialty/-ies, number of years 
within the management of PD and APD patients, number of years working at current 
institution, observance of standard treatment algorithm/established guidelines, overall 
preference on LCIG as monotherapy vs. LCIG plus add-on PD medication, and years of 
experience and number of patients with LCIG, DBS or CSAI.
9.2.7.3
Patient Demographics and socio-demographics
The physician will collect patient demographic information and record it on the eCRF. 
The demographic information includes age, sex, race and ethnicity, and education (where 
applicable and allowed).
Socio-demographic data to be collected before LCIG initiation and at the patient visit and 
includes information on living situation, current primary occupation, and the need of a 
caregiver (and extent of care needed)
9.2.7.4
Medical History and PD History
A complete medical history (PD and non-PD) will be obtained and recorded in the eCRF 
as available from the patient files. Information on PD includes phenotype, date of first PD 
Version 1.0   14th June 2017
28

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
diagnosis, year of first occurrence of motor fluctuations, percentage and daily hours spent 
in off state or spent in on-state with troublesome/non-troublesome dyskinesia, presence of 
PD symptoms (motor and non-motor), Unified Parkinson’s Disease Rating Scale 
(UPDRS), Modified Hoehn & Yahr stage (UPDRS part V), and PD-related comorbidities.
9.2.7.5
Previous PD medication and add-on PD treatment during 
LCIG Treatment
Data on previous PD medication (right before initiation of LCIG treatment) will include
date of drug initiation and/discontinuation, reason for its discontinuation, drug name, total 
dose per day, posology, and attempts of previous device-aided therapies (e.g., CSAI,
DBS).
Data on add-on PD medication upon LCIG initiation or during LCIG treatment will 
include date of drug initiation/discontinuation, drug name, total dose per day, posology, 
tapering* process (duration and posology), starting and end date of LCIG titration,
reasons for add-on drug therapy (severity and frequency), timing of add-on drug 
(during/outside of infusion hours).
Levodopa equivalent daily dose (LEDD) table published by Tomlinson, et al will be used 
to calculate LEDD. [47]. Each PD medication amount should be multiplied by the 
appropriate value to obtain the corresponding LEDD. Adding together the corresponding 
LEDD for each PD medication, will be providing the total LEDD. 
*The term “tapering” is used within this study in the context of drug treatment. It refers to the process of 
reducing a certain drug dosage incrementally (over a few days or weeks), instead of its abrupt 
discontinuation. For some PD medications a tapering process is needed to avoid a withdrawal syndrome
9.2.7.6
Concomitant Disease and Medication
Information on concomitant disease and medication (non-PD treatment) will be collected 
and reported in the eCRF, including drug name, indication, start/stop date, and dosages.
Version 1.0   14th June 2017
29

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.2.7.7
LCIG Treatment
Information on LCIG treatment from initiation until the day of the visit will be 
documented in the eCRF, including reason(s) for initiation of LCIG treatment, date of 
introduction of LCIG, use of nasojejunal tube, date of PEG-J procedure, date of titration
and duration of titration process, infusion settings (infusion time, morning dose, 
continuous infusion rate, total daily dose) and dose modification (number of dosage 
changes, new infusion settings or temporary interruptions in LCIG daily infusion rate and 
reasons for dosage adjustment).
A LCIG substantial dose adjustment is defined as any increase or decrease of the total 
daily LCIG dose by more than 20% of total daily dose.
LCIG monotherapy is defined as being treated with LCIG as the only PD medication that 
the patient is taking during the LCIG infusion hours. LCIG long term monotherapy is
defined as a time period of at least 12 months of continuous LCIG monotherapy.
9.2.7.8
Current APD Status at study visit
x
Parkinson’s disease status will be measured by the physician using the following 
scales: mentation/behaviour/mood (UPDRS I), activities of daily living (UPDRS II),
motor examination (UPDRS III), complications of therapy (UPDRS IV) and Modified 
Hoehn and Yahr Stage (UPDRS V),non-motor symptoms (NMSS) will be recorded
and Mini-Mental State Examination (MMSE).
The patient will be requested to fill in the following questionnaires:
x
Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease- Rating 
Scale (QUIP-RS) 
x
Parkinson’s disease Sleep Scale Version 2 (PDSS-2).
Version 1.0   14th June 2017
30

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.2.7.9
Healthcare Resource Utilization
The HCRU Questionnaire will contain questions on the occupational status, nursing home 
visits, hospitalizations, emergency care visits, caregiver support, including the patient’s 
opinion on PD medication as retrieved by the following questionnaires, which the patient 
will be requested to complete:
x
Beliefs Medication Questionnaire (BMQ)
In addition, the patient/caregiver will be requested to state their overall preference on 
LCIG as a monotherapy vs. LCIG plus add-on PD medication.
9.2.7.10
Quality of Life
In order to assess the patient’s quality of life, the patient will be asked to complete the 
Parkinson’s disease Quality of Life Questionnaire (PDQ-8).
Version 1.0   14th June 2017
31

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Questionnaire (BMQ)
Adverse events, 
pregnancies
x
Product complaints
x
9.3
Variables
9.3.1
Safety Variables
The physician will be asked to document all AEs, product complaints and pregnancies on
eCRFs (Section 11.1 and 11.2)
SAEs (Section 11.1) and product complaints (PCs, Section 11.2) as defined and 
pregnancies that have occurred from the time the physician obtains the patient’s 
authorization to use and disclose information must be reported to AbbVie within 24 hours 
of the study visit.
In addition, any prior suspected adverse reactions (adverse events considered to be likely 
related to an AbbVie product) identified in the patient’s file should be reported (Section 
11.1.5.1). 
9.3.2
Clinical variables
Information about the previous PD medication, and add-on PD medication and LCIG 
infusion settings will be retrospectively collected from patient`s medical records.
Actual Parkinson's disease status and motor symptoms/motor complications will be 
measured using the following tools: 
x
Duration of OFF time and dyskinesia (hours during the day prior to the clinical 
visit) as reported by the patient
x
UPDRS Parts III (motor evaluation) and IV (Treatment complication)
The following health outcomes will be measured using the following tools: 
x
UPDRS Part I (evaluation of mentation, behavior, and mood)
x
UPDRS Part II (self-evaluation of the activities of daily living (ADLs))
Version 1.0   14th June 2017
33

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
x
UPDRS Part V (Modified Hoehn and Yahr stage of severity of Parkinson's 
disease)
x
PDQ-8 (Parkinson´s Disease Questionnaire) to evaluate PD patient’s quality of 
life.
The following Non-motor symptoms including sleep/daytime sleepiness, impulse control 
disorders and mental status will be measured using the following tools:
x
Non-motor Symptoms Scale (NMSS)
x
Parkinson´s Disease Sleep Scale-2 (PDSS-2)
x
Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease-
Rating Scale (QUIP-RS)
x
Mini-Mental State Examination (MMSE)
The following healthcare utilization resources and patient’s beliefs on medication will be 
measured using the following tools:
x
HCRU (Healthcare resource utilization questionnaire)
x
Beliefs Medication questionnaire (BMQ)
9.4
Data Sources
9.4.1
Source documents
Source documents are defined as original documents, data and records. These may include 
hospital records, clinical and office charts, laboratory data/information, pharmacy 
dispensing and other records, recorded data from automated instruments, microfiches, 
photographic negatives, microfilm or magnetic media and/or x-radiographs. Data 
collected during this PMOS must be recorded on the appropriate source documents. The 
only exception will be for patient/caregiver-completed questionnaires. (i.e. PDSS-2, PDQ-
8, QUIP-RS). There will be no corresponding source documentation for the latter, because 
the patient/caregiver completes the forms directly on the paper questionnaire (that is, these 
questionnaires are the source data). Patient/caregiver self-administered questionnaires will 
be completed on paper forms, double-checked for completeness by the site personal 
Version 1.0   14th June 2017
34

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
participating in the study and then submitted to the designated CRO GKM for data entry 
into the eCRF system.
The PMOS physician/institution will permit PMOS-related monitoring, audits, 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) review, and 
regulatory inspection(s), providing direct access to source documents. 
9.4.2
Product supply
Since this is a PMOS, the patient will be treated in accordance with the physician’s usual 
and customary medical practice. AbbVie will not provide any medication or therapy for 
this PMOS. 
9.4.3
Health Outcomes
9.4.3.1
Unified Parkinson’s Disease Rating Scale (UPDRS)
The Unified Parkinson's Disease Rating Scale (UPDRS) [49] is an Investigator-used tool 
to follow the longitudinal course of Parkinson's disease. The UPDRS assessment will be 
performed by an experienced rater. Rater training will be provided by the Sponsor as 
appropriate.
The UPDRS is includes of the following sections: 
x
Part I – Mentation, Behaviour, and Mood; total score range 0-16
x
Part II – Activities of Daily Living (ADL); total score range 0-52
x
Part III – Motor Examination; total score range 0-108
x
Part IV – Complications of Therapy; total score range 0-23
o
Dyskinesias and Dystonia (Part IV, items 32-35); total score 0-13
o
Motor fluctuations (Part IV, items 36-39); total score range 0-7
o
Other complications (Part IV, items 40-42); total score range 0-3
x
Part V – Modified Hoehn & Yahr Stage
Version 1.0   14th June 2017
35

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
The dimensions are evaluated through a physical examination and interview carried out 
by the neurologist. The patient score can be between 0 and 199, where 199 points 
indicates complete disability. In this PMOS, all five sections of the UPDRS will be used. 
9.4.3.2
Non-Motor Symptoms Scale (NMSS)
The NMSS is a comprehensive investigator-completed validated tool measuring a broad 
range of non-motor symptoms in PD patients. The scale is aimed to be practical and 
quantitative, encompassing the whole range of non-motor symptoms experienced by 
people with PD. The NMSS measures the frequency and severity of these symptoms and 
comprises 30 questions covering 9 domains of patient symptom experience 
(cardiovascular/falls, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, 
attention/memory, GI tract, urinary, sexual function, and miscellaneous [pain, taste/smell, 
weight change, excessive sweating]) [50, 51]. The NMSS measures the burden of non-
motor symptoms by weighting each symptom by its frequency and severity; thereby, 
providing a quantitative measure that captures infrequent but severe symptoms (e.g., 
hallucinations) and less serious but frequent symptoms (e.g., fatigue, constipation) and 
provides the overall global burden for patients. Scores are calculated for each domain as 
well as a total score. Severity and frequency are rated using a 4-point scale ranging from 0 
(none) to 3 (severe; major source of distress or disturbance to subject) for severity and
from 1 (rarely) to 4 (very frequent [daily or all the time]) for frequency. The total NMSS 
score ranges from 0 to 360. 
9.4.3.3
Parkinson’s Disease Questionnaire (PDQ-8)
The PDQ-8 [52] is a disease-specific instrument designed to measure aspects of quality of 
life 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 and is a patient 
reported outcome measure. 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).
Version 1.0   14th June 2017
36

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
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.
9.4.3.4
Parkinson’s Disease Sleep Scale-2 (PDSS-2)
Although a number of scales exist in evaluating sleep disturbance, only 3 are endorsed 
and recommended by the Movement Disorders Society [53]. One such scale specific for 
Parkinson's disease is the Parkinson's Disease Sleep Scale (PDSS), and its modified 
version, the PDSS-2. The purpose of the PDSS-2 scale is to characterize the various 
aspects of nocturnal sleep problems in PD patients. The PDSS-2 instrument has been 
shown to be reliable, valid, precise, and a potentially treatment responsive tool for 
measuring nocturnal disabilities and sleep disorders in PD [54]. PDSS-2 consists of 15 
questions evaluating motor and non-motor symptoms at night and upon wakening, as well 
as disturbed sleep grouped into 3 domains: motor symptoms at night (5 items), PD 
symptoms at night (5 items), and disturbed sleep (5 items). Specifically, questions assess 
overall sleep quality, insomnia, sleep fragmentation, Restless Legs Syndrome (RLS) and 
periodic limb movements of sleep (PLMS), REM (rapid eye movement) sleep behaviour 
disorder (RBD), hallucinations, nocturia, nocturnal immobility, pain and cramps, morning 
akinesia, cramps and tremor, and sleep apnea. The PDSS-2 was developed from the PDSS 
based upon the need for a treatment/measuring tool containing PD-specific sleep 
disorders. The instrument was extended to address specific sleep disturbances such as 
RLS, akinesia, pain, and sleep apnea. Daytime sleepiness was removed from the PDSS-2,
as it is a more complex PD symptom. To increase ease of use, the visual analogue scale of 
the PDSS was transformed into a frequency measure in the PDSS-2. The frequency is 
assessed for the 15 sleep problems based on a 5-point Likert-type scale (ranging from 0 
[never] to 4 [very often]). Scores are calculated for each domain as well as a total score. 
The recall period is for the previous week before the study visit. 
Version 1.0   14th June 2017
37

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.4.3.5
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s disease- Rating Scale (QUIP-RS)
The QUIP-RS is a fairly novel self-administered rating scale for the evaluation of the 
symptoms of impulsive compulsive disorders (ICD). ICD may occur in PD patients under 
dopaminergic drug therapy, also called dopaminergic dysregulation syndrome [55, 56].
QUIP-RS has been shown to have very good sensitivities and appears to be a valid 
instrument in the evaluation of ICD in patients with APD [57].
The QUIP-RS is completed by the patient. The QUIP-RS uses a 5-point Likert scale upon 
which each symptoms is rated based on frequency (i.e. [0] = not at all, [1] = rarely, etc.). 
There are four primary questions, related to the 4 ICDs (compulsive gambling, buying, 
eating, and sexual behaviour), and 3 related disorders (medication use, punding, and 
hobbyism). The total QUIP-RS score ranges from 0 to 112 [57].
9.4.3.6
Healthcare Resource Utilization (HCRU)
The HCRU questionnaire will contain questions on the occupational status, nursing home 
visits, hospitalizations/emergency care visits and reason, caregiver support, patient´s 
opinion on PD medication (Belief Medication questionnaire -BMQ-)) and other items 
with respect to healthcare resource utilization.
x
The Beliefs Medication Questionnaire (18-items BMQ) is a tool for screening 
patients’ beliefs, attitudes and concerns regarding their medication. It consists of a 
general section, which assesses general beliefs about medicines, and  a specific 
section which comprises factors assessing beliefs about necessity and concerns 
about the currently prescribed medications [58].
9.4.3.7
Mini-Mental State Examination (MMSE)
The MMSE [59] is a brief, 30-point questionnaire, administered by a trained rater, which 
provides a quantitative measure of cognitive mental status in adults and is widely used to 
screen for cognitive impairment and to estimate the severity of cognitive impairment at a 
given point in time, to follow the course of cognitive changes in a patient over time, and 
Version 1.0   14th June 2017
38

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
to document response to treatment.  In this study, MMSE will be used to evaluate 
cognition status at cross-sectional visit, and if available to collect it before starting LCIG 
treatment.
9.5
Study Size
The primary objective of this PMOS is to estimate the percentages of APD patients on 
LCIG monotherapy right after LCIG initiation and at 3, 6, 9, and 12 months, respectively.
Sample size calculation was based on pre-defined precision of the estimators, expressed as 
the maximum length of the corresponding two-sided 95% confidence intervals. In order to 
achieve a precision of ± 5% (i.e. the confidence intervals are not wider than 10%), and 
considering an underlying percentage of 50% (i.e. the percentage which leads to the 
largest sample size), at least 385 (evaluable) patients are necessary. 
In this PMOS, only a small number of non-evaluable patients are expected. Therefore, it is 
planned to include a total number of approximately 400 patients.
9.6
Data Management
CRFs must be completed for each patient enrolled in this PMOS. These forms will be 
used to transmit information collected during the PMOS to AbbVie and regulatory 
authorities, as applicable. The CRF data for this PMOS are being collected with an 
electronic data capture (EDC) system, Rave®, provided by the technology vendor 
Medidata Solutions Incorporated, NY, USA. The EDC system and the PMOS-specific 
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 PMOS-specific eCRFs will be conducted by AbbVie and will be 
maintained in the Trial Master File at AbbVie. The investigator will document patient 
data in his/her own patient files. Questionnaires filled in by the patients will be source 
data (e.g., QUIP-RS, PDQ-8, PDSS-2, BMQ). All eCRF data required by this protocol 
will be recorded in the EDC system. All data entered into the eCRF will be supported by 
source documentation, except for questionnaires that are completed by the physicians
Version 1.0   14th June 2017
39

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
(UPDRS, NMSS). Only the investigator or an authorized member of the investigator's 
staff will able to change or correct eCRF data. All changed information, including the date 
and person performing the changes, will be available via the EDC audit trail. For any 
eCRF correction, a reason for the alteration must 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 PMOS in order to verify eCRF entries. The Principal 
Investigator will review the eCRFs for completeness and accuracy and provide his or her 
electronic signature and date to eCRFs as evidence thereof. Access to the web-based EDC 
system for the duration of the PMOS is protected by an individual account (consisting of 
username and password). This access will be removed from investigator sites at the end of 
the site's participation in the PMOS. Data will be subject to automatic and manual 
plausibility checks and implausible data will be queried by means of queries in the EDC 
system; in case of technical issues, paper based query forms will be sent to the sites.
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.
9.7
Data Analysis
Summary of data collected from retrospective patient´s medical records and single study 
visit will be presented using descriptive statistics. 
Quantitative data (e.g. age) will be analyzed by the statistical parameters valid N, missing 
N, mean, standard deviation (SD), and selected quantiles: minimum (0%), lower quartile 
(25%), median (50%), upper quartile (75%), and maximum (100%). If indicated by the 
data, an additional frequency distribution will be supplied after appropriate grouping of 
data.
Qualitative (e.g. gender) and categorical variables (e.g. individual items of questionnaires) 
will be presented by (absolute and relative) frequency distributions. For categorical 
variables associated with score values, the mean will be calculated as well.
Version 1.0   14th June 2017
40

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Two-sided 95% confidence intervals will be provided for primary and secondary 
endpoints defined by proportions. Confidence intervals will also be calculated for 
differences between pre-defined groups of patients, if appropriate (e.g. LCIG as 
monotherapy vs. LCIG plus add-on therapy).
Logistic regression and subgroup analyses will be applied to investigate the impact of 
potential prognostic factors for LCIG monotherapy. Potential prognostic factors used for 
the regression model will include demographic variables (ie. age, gender, race) and 
baseline disease characteristics at LCIG initiation (PD duration, hours of OFF time, hours 
of dyskinesia, Levodopa equivalent daily dosage).
Details of statistical methods will we presented in a separate statistical analysis plan 
(SAP). All statistical analyses will be carried out by means of the SAS® package (version 
9.4 or higher).
9.8
Quality Control
The personnel at each PMOS site may be trained on the protocol and PMOS procedures 
by a CRA at a site training visit, via telephone or on-site.
Throughout the PMOS, the CRO and AbbVie will periodically follow-up with sites to 
ensure that SAEs and PCs are being reported.
All PMOS data will be entered into the eCRF which will be accessed via a web-based 
EDC system. Any necessary corrections will be made to the database and documented via 
queries, source data clarification form or audit trail. A manual review of elected line 
listings will also be performed at the end of the PMOS. A clinical monitor working on 
behalf of AbbVie will perform a final site closure visit when the site or study is closed.
Version 1.0   14th June 2017
41

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9.9
Limitations of the Research Methods
The primary limitation of this PMOS is that it is performed in an open-label, non-
controlled and non-randomized design with mainly retrospective data capturing. Thus, 
selection and reporting bias cannot be excluded. In order to minimize these biases, all 
eligible patients shall be enrolled in a consecutive manner.
Moreover, as only patients on current LCIG therapy are included, data of patients who 
discontinued treatment will not be collected. Therefore, comprehensive safety conclusions 
may not be drawn from the study results.
Finally as the study aims to identify treatment predictors based on patient´s and 
physician´s profiles; however it can be influenced by LCIG country specific prescription 
or reimbursement status. Therefore, country origin would be taken into account when 
analyzing treatment predictors.  
9.10
Other Aspects
Not applicable
10.0
Protection of Human Subjects
A signed and dated Authorization for Use/Disclosure of Data (AUDD)/informed consent 
form (ICF) will be obtained from patients or their legal authorized representative (LAR) 
before the release of any information or participation in the PMOS. Before the patient 
AUDD/ICF is obtained, the physician or designee will explain to the patient/caregiver 
(LAR) the nature and purpose of the PMOS and the data to be provided to the Sponsor.
An AUDD/ICF template will be provided to the investigator by AbbVie, which can be 
modified according to local requirements. After the AUDD/ICF is signed, the original 
form will be placed in the patient's medical record and a signed copy should be given to
the patient/caregiver.
Information that refers to the identity of patients will be considered confidential for all 
purposes. Patient identity may not be revealed or divulged. The physician will maintain a 
Version 1.0   14th June 2017
42

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
confidential patient identification code list of all patients enrolled in the PMOS (by name 
and patient number). This list will be maintained at the site and will not be retrieved by 
AbbVie.
11.0
Management and Reporting of 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.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 12). For adverse events, please refer to Sections 11.1.1
through 11.1.6. For product complaints, please refer to Section 12.
11.1
Medical Complaints
11.1.1
Adverse Event Definition and Serious Adverse Event 
Categories
An adverse event (AE) is defined as any untoward medical occurrence in a patient, which 
does not necessarily have a causal relationship with their 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 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 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.
If an adverse event meets any of the following criteria, it is considered a serious adverse 
event (SAE):
Version 1.0   14th June 2017
43

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Death of Patient:
An event that results in the death of a patient.
Life-Threatening:
An event that, in the opinion of the investigator, 
would have resulted in immediate fatality if medical 
intervention had not been taken. This does not include 
an event that would have been fatal if it had occurred 
in a more severe form.
Hospitalization:
An event that results in an admission to the hospital 
for any length of time. This does not include an 
emergency room visit or admission to an outpatient 
facility.
Prolongation of 
Hospitalization:
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay.
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 
patient. 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 patient and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, 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.
Version 1.0   14th June 2017
44

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
11.1.2
Severity
The following definitions will be used to rate the severity for any adverse event being 
collected as an endpoint/data point in the study and for all serious adverse events.
Mild:
The adverse event is transient and easily tolerated by the patient.
Moderate:
The adverse event causes the patient discomfort and interrupts the 
patient's usual activities.
Severe:
The adverse event causes considerable interference with the 
patient's usual activities and may be incapacitating or life 
threatening.
11.1.3
Relationship to Pharmaceutical Product
The following definitions will be used to assess the relationship of the adverse event to 
the use of product:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient
evidence (information) to suggest a causal relationship
If no reasonable possibility of being related to product is given, an alternate etiology must 
be provided for the adverse event.
11.1.4
Serious Adverse Event Collection Period
Serious adverse events will be reported to AbbVie from the time the physician obtains the 
patient's authorization to use and disclose information (or the patient's informed consent) 
Version 1.0   14th June 2017
45

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
specifying the suspected adverse reaction was identified during retrospective review of the 
study. Those events are collected only on the “retrospective data collection events 
section” of the EDC system.
11.1.6
Pregnancy Reporting
In the event of a pregnancy occurrence in the patient, the physician will notify AbbVie via 
the EDC system within 24 hours of the physician becoming aware of the pregnancy.
Pregnancy in a study subject is not considered an adverse event. The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion, is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
12.0
Product Complaint
12.1.1
Definition
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example: printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
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.
Version 1.0   14th June 2017
47

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.
12.1.2
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 local Product 
Complaint reporting practices. Please refer to the contact person identified in Section 14 
(Affiliate Agreement page) of the protocol. 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 involving a non-Sponsor investigational product and/or device should 
be reported to the identified contact or manufacturer, as necessary per local regulations.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, 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.
13.0
Plans for Disseminating and Communicating Study 
Results
At the end of the PMOS, a PMOS report and a publication will be written. The required 
standard PMOS report template must be followed. This report will contain a description 
Version 1.0   14th June 2017
48

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
of the objectives of the PMOS, the methodology of the PMOS and its results and 
conclusions. The PMOS report must be treated as the confidential property of AbbVie and 
may not be released to unauthorized people in any form (publications or presentations) 
without express written approval from AbbVie. The results of this PMOS will be 
published by AbbVie or by the participating investigators only after agreement with 
AbbVie.
Version 1.0   14th June 2017
49

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
14.0
References
1.
Pringsheim, T., et al., The prevalence of Parkinson's disease: a systematic review 
and meta-analysis. Mov Disord, 2014. 29(13): p. 1583-90.
2.
Chase, T.N., M.M. Mouradian, and T.M. Engber, Motor response complications 
and the function of striatal efferent systems. Neurology, 1993. 43(12 Suppl 6): p. 
S23-7.
3.
Gershanik, O. and P. Jenner, Moving from continuous dopaminergic stimulation to 
continuous drug delivery in the treatment of Parkinson’s disease. European 
journal of neurology, 2012. 19(12): p. 1502-1508.
4.
Nyholm, D., et al., Duodenal levodopa infusion monotherapy vs oral 
polypharmacy in advanced Parkinson disease. Neurology, 2005. 64(2): p. 216-
223.
5.
van Laar, T., Levodopa-induced response fluctuations in patients with Parkinson’s 
disease. CNS drugs, 2003. 17(7): p. 475-489.
6.
JT Slevin, JC Martinez-Castrillo, R Krueger, C Hall, J Dubow, K Chatamra, 
Clinical Experience Tapering Anti-Parkinsonian Medication Pre- and Post-
Initiation of Levodopa-Carbidopa Intestinal Gel, Presented at the Movement 
Disorder Society's Annual International Congress of Parkinson's Disease and 
Movement Disorders, Stockholm June 8-12, 2014.
7.
Olanow, C.W., 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. The Lancet Neurology, 2014. 
13(2): p. 141-149.
8.
Fernandez, H.H., et al., Levodopa-carbidopa intestinal gel in advanced 
Parkinson's disease: final 12-month, open-label results. Mov Disord, 2015. 30(4): 
p. 500-9.
9.
Lopiano, L., et al., Motor outcomes in patients with advanced Parkinson’s disease 
treated with levodopa/carbidopa intestinal gel in Italy: an interim analysis from 
the GREENFIELD observational study. Neurological Sciences, 2016. 37(11): p. 
1785-1792.
10.
Antonini, A., et al., Global long-term study on motor and non-motor symptoms 
and safety of levodopa-carbidopa intestinal gel in routine care of advanced 
Parkinson's disease patients; 12-month interim outcomes. Parkinsonism & related 
disorders, 2015. 21(3): p. 231-235.
11.
W. Poewe, T.K., B. Bermans, P. Odin, A. Antonini, O. Bajenaru, K. Onuk, A. 
Yegin, L. Bergmann, K.R. Chaudhuri, Levodopa-carbidopa intestinal gel in 
routine care of advanced Parkinson’s disease patients: Final long-term efficacy 
Version 1.0   14th June 2017
50

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
results on motor complications from the GLORIA registry. Abstract Number 1981, 
Presentation at 20th International Congress of the International Parkinson and 
Movement Disorder Society, 19-23 June, 2016, Berlin, Germany 
12.
de Rijk, M.d., et al., Prevalence of parkinsonism and Parkinson's disease in 
Europe: the EUROPARKINSON Collaborative Study. European Community 
Concerted Action on the Epidemiology of Parkinson's disease. Journal of 
Neurology, Neurosurgery & Psychiatry, 1997. 62(1): p. 10-15.
13.
Scheife, R.T., et al., Impact of Parkinson's disease and its pharmacologic 
treatment on quality of life and economic outcomes. American Journal of Health-
System Pharmacy, 2000. 57(10): p. 953-962.
14.
Tanner, C.M. and S.M. Goldman, Epidemiology of Parkinson's disease.
Neurologic clinics, 1996. 14(2): p. 317-335.
15.
Louis, E.D., et al., Mortality from Parkinson disease. Archives of Neurology, 
1997. 54(3): p. 260-264.
16.
Agid, Y., et al., Are dopaminergic neurons selectively vulnerable to Parkinson's 
disease? Advances in neurology, 1993. 60: p. 148-164.
17.
Gelb, D.J., E. Oliver, and S. Gilman, Diagnostic criteria for Parkinson disease.
Archives of neurology, 1999. 56(1): p. 33-39.
18.
Calne, D., B. Snow, and C. Lee, Criteria for diagnosing Parkinson's disease.
Annals of neurology, 1992. 32(S1): p. S125-S127.
19.
Hughes, A.J., et al., What features improve the accuracy of clinical diagnosis in 
Parkinson's disease A clinicopathologic study. Neurology, 1992. 42(6): p. 1142-
1142.
20.
Hughes, A.J., et al., Accuracy of clinical diagnosis of idiopathic Parkinson's 
disease: a clinico-pathological study of 100 cases. Journal of Neurology, 
Neurosurgery & Psychiatry, 1992. 55(3): p. 181-184.
21.
Rajput, A., B. Rozdilsky, and A. Rajput, Accuracy of clinical diagnosis in 
parkinsonism—a prospective study. Can J Neurol Sci, 1991. 18(3): p. 275-278.
22.
Olanow, C.W., R.L. Watts, and W.C. Koller, An algorithm (decision tree) for the 
management of Parkinson's disease (2001): treatment guidelines. Neurology, 
2001. 56(11 Suppl 5): p. S1-s88.
23.
Chase, T.N., Levodopa therapy consequences of the nonphysiologic replacement 
of dopamine. Neurology, 1998. 50(5 Suppl 5): p. S17-S25.
24.
Olanow, C.W. and J.A. Obeso, Preventing levodopa-induced dyskinesias. Annals 
of neurology, 2000. 47(4 Suppl 1): p. S167-76; discussion S176-8.
25.
Lang, A.E. and A. Lozano, Medical progress: Parkinson's Disease (second of two 
parts). New England Journal of Medicine, 1998. 339: p. 1130-1143.
26.
Lang, A.E. and A.M. Lozano, Parkinson's disease. New England Journal of 
Medicine, 1998. 339(15): p. 1044-1053.
27.
Pierantozzi, M., et al., Helicobacter pylori eradication and l-dopa absorption in 
patients with PD and motor fluctuations. Neurology, 2006. 66(12): p. 1824-1829.
Version 1.0   14th June 2017
51

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
28.
Antonini, A., et al., A 5-year prospective assessment of advanced Parkinson 
disease patients treated with subcutaneous apomorphine infusion or deep brain 
stimulation. J Neurol, 2011. 258(4): p. 579-85.
29.
Hilker, R., A. Antonini, and P. Odin, What is the best treatment for fluctuating 
Parkinson's disease: continuous drug delivery or deep brain stimulation of the 
subthalamic nucleus? J Neural Transm (Vienna), 2011. 118(6): p. 907-14.
30.
Wright, B.A. and C.H. Waters, Continuous dopaminergic delivery to minimize 
motor complications in Parkinson's disease. Expert Rev Neurother, 2013. 13(6): p. 
719-29.
31.
A Cenci, M., K. E Ohlin, and P. Odin, Current options and future possibilities for 
the treatment of dyskinesia and motor fluctuations in Parkinson's disease. CNS & 
Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & 
Neurological Disorders), 2011. 10(6): p. 670-684.
32.
Grandas, F., Subcutaneous infusions of apomorphine: a reappraisal of its 
therapeutic efficacy in advanced Parkinson's disease. Expert Rev Neurother, 
2013. 13(12): p. 1343-53.
33.
Kleiner-Fisman, G., et al., Subthalamic nucleus deep brain stimulation: summary 
and meta-analysis of outcomes. Mov Disord, 2006. 21 Suppl 14: p. S290-304.
34.
Williams, A., et al., Deep brain stimulation plus best medical therapy versus best 
medical therapy alone for advanced Parkinson's disease (PD SURG trial): a 
randomised, open-label trial. Lancet Neurol, 2010. 9(6): p. 581-91.
35.
Bredberg, E., et al., Intraduodenal infusion of a water-based levodopa dispersion 
for optimisation of the therapeutic effect in severe Parkinson's disease. European 
journal of clinical pharmacology, 1993. 45(2): p. 117-122.
36.
Nilsson, D., et al., Long̺term intraduodenal infusion of a water based 
levodopa̺carbidopa dispersion in very advanced Parkinson's disease. Acta 
neurologica scandinavica, 1998. 97(3): p. 175-183.
37.
Nyholm, D. and S.-M. Aquilonius, Levodopa infusion therapy in Parkinson 
disease: state of the art in 2004. Clinical neuropharmacology, 2004. 27(5): p. 245-
256.
38.
Nilsson, D., D. Nyholm, and S.M. Aquilonius, Duodenal levodopa infusion in 
Parkinson's disease̽long̺term experience. Acta neurologica scandinavica, 2001. 
104(6): p. 343-348.
39.
Rahnemai-Azar, A.A., et al., Percutaneous endoscopic gastrostomy: Indications, 
technique, complications and management. World Journal of Gastroenterology : 
WJG, 2014. 20(24): p. 7739-7751.
40.
AbbVie Ltd., Duodopa 20 mg/ml + 5 mg/ml, intestinal gel. Summary of Product 
Characteristics United Kingdom. 2016.
Version 1.0   14th June 2017
52

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
41.
Annic, A., et al., Continuous dopaminergic stimulation by Duodopa in advanced 
Parkinson's disease: Efficacy and safety. Revue neurologique, 2008. 165(8-9): p. 
718-727.
42.
Antonini, A., et al., Duodenal levodopa infusion improves quality of life in 
advanced Parkinson’s disease. Neurodegenerative Diseases, 2008. 5(3-4): p. 244-
246.
43.
Nyholm, D., et al., Levodopa pharmacokinetics and motor performance during 
activities of daily living in patients with Parkinson's disease on individual drug 
combinations. Clinical neuropharmacology, 2002. 25(2): p. 89-96.
44.
Nyholm, D., et al., Enteral levodopa/carbidopa infusion in advanced Parkinson 
disease: long-term exposure. Clinical neuropharmacology, 2008. 31(2): p. 63-73.
45.
Slevin, J.T., 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. Journal of Parkinson's disease, 2015. 
5(1): p. 165-174.
46.
DG Standaert, JT Boyd, C Zadikoff , WZ Robieson, J Dubow, K Chatamra.
Clinical Experience of Levodopa-Carbidopa Intestinal Gel Treatment With or 
Without Adjunctive Parkinson’s Disease Medications. Presented at the Movement 
Disorder Society's Annual International Congress of Parkinson's Disease and 
Movement Disorders, Stockholm June 8-12, 2014.
47.
Buhmann, C., et al., Levodopa/carbidopa intestinal gel (LCIG) infusion as mono-
or combination therapy. J Neural Transm (Vienna), 2017. First Online available
22 February 2017.
48.
Tomlinson, C.L., et al., Systematic review of levodopa dose equivalency reporting 
in Parkinson's disease. Movement disorders, 2010. 25(15): p. 2649-2653.
49.
Martínez̺Martín, P., et al., Unified Parkinson's disease rating scale 
characteristics and structure. Movement disorders, 1994. 9(1): p. 76-83.
50.
Chaudhuri, K.R., et al., The metric properties of a novel non̺motor symptoms 
scale for Parkinson's disease: results from an international pilot study. Movement 
Disorders, 2007. 22(13): p. 1901-1911.
51.
Chaudhuri, K.R., et al., International multicenter pilot study of the first 
comprehensive self̺completed nonmotor symptoms questionnaire for Parkinson's 
disease: The NMSQuest study. Movement Disorders, 2006. 21(7): p. 916-923.
52.
Jenkinson, C., R. Fitzpatrick, and V. Peto, The Parkinson’s dissease 
questionnaire. User manual for the PDQ–39, PDQ–8 and PDQ summary index. 
1998. Oxford: Health Services Research Unit, University of Oxford.
53.
Högl, B., et al., Scales to assess sleep impairment in Parkinson's disease: critique 
and recommendations. Movement Disorders, 2010. 25(16): p. 2704-2716.
54.
Trenkwalder, C., et al., Parkinson's disease sleep scale̾validation of the revised 
version PDSS̺2. Movement Disorders, 2011. 26(4): p. 644-652.
Version 1.0   14th June 2017
53

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
55.
Giovannoni, G., et al., Hedonistic homeostatic dysregulation in patients with 
Parkinson's disease on dopamine replacement therapies. J Neurol Neurosurg 
Psychiatry, 2000. 68(4): p. 423-8.
56.
Evans, A.H., et al., Punding in Parkinson's disease: its relation to the dopamine 
dysregulation syndrome. Mov Disord, 2004. 19(4): p. 397-405.
57.
Weintraub, D., et al., Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson's Disease-Rating Scale. Mov Disord, 2012. 27(2): p. 242-7.
58.
Horne, R., J. Weinman, and M. Hankins, The beliefs about medicines 
questionnaire: The development and evaluation of a new method for assessing the 
cognitive representation of medication. Psychology & Health, 1999. 14(1): p. 1-
24.
59.
Folstein SE, McHugh PR.  Mini-mental state:  a practical method for grading the 
cognitive state of patients for the clinician.  J Psychiatric Res.  1975;12:189-98.
Version 1.0   14th June 2017
54

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
15.0
Affiliate Agreement page
AbbVie
COSMOS – P16-831 - COmedication Study assessing Mono- and cOmbination therapy 
with levodopa-carbidopa inteStinal gel
Country < XXXXXXXX>
Sponsor:
Name of Medical Director: 
Address: 
Phone: 
Fax:     
Report safety information to:
Name: 
Address: 
Phone: 
Fax:     
Email:
Report product complaints to:
Name: 
Address: 
Phone: 
Fax:    
Email:
Version 1.0   14th June 2017
55

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Requirements for non-interventional studies per local laws and regulations:
Competent Authority approval                            

Competent Authority notification                  

Competent Authority involvement not required

Competent Authority, other: 
_______________________________________________________
Ethics Committee approval                                  

Ethics Committee notification                              

Ethics Committee involvement not required        

Written Patient Informed Consent required:          
 No       Yes      
<Name here>
Affiliate Medical Director
Signature 
Date
Version 1.0   14th June 2017
56

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Annex 15.
Patient Questionnaires
A.
Parkinson’s Disease Quality of Life Questionnaire (PDQ-8)
Due to having Parkinson’s disease,  how often during the last month have you…
Please check one box for each question
Never
Occasionally
Sometimes
Often
Always
or cannot 
do at all
1.
Had difficulty getting around in public places?
2.
Had difficulty dressing yourself?
3.
Felt depressed?
4.
Had problems with your close personal 
relationships?
5.
Had problems with your concentration, e.g. when 
reading or watching TV?
6.
Felt unable to communicate with people properly?
7.
Had painful muscle cramps or spasms?
8.
Felt embarrassed in public due to having 
Parkinson's disease?
Please check that you have ticked one box for each question.
Thank you for completing the questionnaire.
Final English PDQ-8.
PDQ-8 © Copyright, Oxford University Innovation Limited 1998. All Rights Reserved.
The authors, being Professor Crispin Jenkinson, Professor Ray Fitzpatrick and Ms Viv Peto, have asserted their moral rights.
Version 1.0   14th June 2017
57

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
B.
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - 
Rating Scale (QUIP-RS)
  
QUIP-RATING SCALE Version 1 0 (7/01/09) Copyright © University of Pennsylvania 2009
Version 1.0   14th June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
58

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
C.
Parkinson's Disease Sleep Scale-2 (PDSS-2)  
 
Please rate the severity of the following based on your experiences during the past week (7 days). 
  
Very often:  This mean 6 to 7 days a week 
Often: This mean 4 to 5 days a week 
Sometimes:  This mean 2 to 3 days a week  
Occasionally: This mean 1 day a week 
Never  
   
1. Overall, did you sleep well during the last week?
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
2. Did you have difficulty falling asleep at night? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
3. Did you have difficulty staying asleep? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
4. Did you have restlessness of legs or arms at night causing disruption of sleep? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
5. Was your sleep disturbed due to an urge to move your legs or arms? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
6. Did you suffer from distressing dreams at night? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
7. Did you suffer from distressing hallucinations at night (seeing or hearing things that do not exist)? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
8. Did you get up a night to urinate? 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
Version 1.0   14th June 2017
59

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
9. Did you feel uncomfortable at night because you were unable to turn around in bed or moved due to 
immobility? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
10. Did you feel pain in your arms or legs which woke you up while sleeping at night?
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
11. Did you have muscle cramps in your arms or legs which woke you up while sleeping at night? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
12. Did you wake early in the morning with painful posturing of arms and legs ? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
13. On waking, did you experience tremor? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
14. Did you feel tired and sleepy after waking in the morning? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
15. Did you wake up at night due to your own snoring or difficulties with breathing? 
 
 
  
 Very Often  
 Often  
 Sometimes  
 Occasionally  
 Never 
 
 
PDSS-2 © Ray Chaudhuri, Claudia Trenkwalder 2010, All rights reserved
 
 
Version 1.0   14th June 2017
60

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
D.
Beliefs Medication Questionnaire (18-item BMQ)
Your views about medicines prescribed for you.
y
We would like to ask you about your personal views about medicines prescribed for you.
y
These are statements other people have made about their medicines.
y
Please indicate the extent to which you agree or disagree with them by checking the appropriate box.
y
There is no right or wrong answers. We are interested in your personal views.
Strongly disagree
disagree
uncertain
agree
Strongly agree
1.
Doctors use too many medicines
2.
Doctors place too much trust on 
medicines
3.
If doctors had more time with 
patients, they would prescribe 
fewer medicines
4.
Natural remedies are safer than 
medicines
5.
Medicines do more harm than good
6.
People who take medicines should 
stop their treatment for a while 
every now and then
7.
Most medicines are addictive
8.
All medicines are poisons
Version 1.0   14th June 2017
61

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Strongly disagree
disagree
uncertain
agree
Strongly agree
9.
my health, at present, depends on 
my medicine
10.
having to take my medicine worries 
me
11.
my life would be impossible without 
my medicine
12.
I sometimes worry about long term 
effects of my medicine
13.
without my medicine I would be 
very ill
14.
my medicine is a mystery to me
15.
my health in the future will depend 
on my medicine
16.
my medicine disrupts my life
17.
I sometimes worry about becoming 
too dependent on my medicine
18.
my medicine protects me from 
becoming worse
Beliefs about Medicines Questionnaire (BMQ Specific-10 & BMQ General-8)© 
 
Version 1.0   14th June 2017
62

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Annex 16.
Physician Questionnaires
A.
Unified Parkinson's Disease Rating Scale (UPDRS)
I. MENTATION, BEHAVIOR AND MOOD
1. Intellectual Impairment
0 = None.
1 = Mild. Consistent forgetfulness with partial recollection of events and no other difficulties.
2 = Moderate memory loss, with disorientation and moderate difficulty handling complex problems.
Mild but definite impairment of function at home with need of occasional prompting.
3 = Severe memory loss with disorientation for time and often to place.
Severe impairment in handling problems.
4 = Severe memory loss with orientation preserved to person only. Unable to make judgements
or solve problems. Requires much help with personal care. Cannot be left alone at all.
2. Thought Disorder (Due to dementia or drug intoxication)
0 = None.
1 = Vivid dreaming.
2 = "Benign" hallucinations with insight retained.
3 = Occasional to frequent hallucinations or delusions; without insight;
could interfere with daily activities.
4 = Persistent hallucinations, delusions, or florrid psychosis. Not able to care for self.
3. Depression
0 = None.
1 = Periods of sadness or guilt greater than normal, never sustained for days or weeks.
2 = Sustained depression (1 week or more).
3 = Sustained depression with vegetative symptoms (insomnia, anorexia, weight loss, loss of interest).
4 = Sustained depression with vegetative symptoms and suicidal thoughts or intent.
4. Motivation/Initiative
0 = Normal.
1 = Less assertive than usual; more passive.
2 = Loss of initiative or disinterest in elective (nonroutine) activities.
3 = Loss of initiative or disinterest in day to day (routine) activities.
4 = Withdrawn, complete loss of motivation.
II. ACTIVITIES OF DAILY LIVING (for both "on" and "off")
5. Speech
0 = Normal.
1 = Mildly affected. No difficulty being understood.
2 = Moderately affected. Sometimes asked to repeat statements.
3 = Severely affected. Frequently asked to repeat statements.
4 = Unintelligible most of the time.
6. Salivation
0 = Normal.
1 = Slight but definite excess of saliva in mouth; may have nighttime drooling.
2 = Moderately excessive saliva; may have minimal drooling.
3 = Marked excess of saliva with some drooling.
4 = Marked drooling, requires constant tissue or handkerchief.
7. Swallowing
0 = Normal.
1 = Rare choking.
2 = Occasional choking.
Version 1.0   14th June 2017
63

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
3 = Requires soft food.
4 = Requires NG tube or gastrotomy feeding.
8. Handwriting
0 = Normal.
1 = Slightly slow or small.
2 = Moderately slow or small; all words are legible.
3 = Severely affected; not all words are legible.
4 = The majority of words are not legible.
9. Cutting food and handling utensils
0 = Normal.
1 = Somewhat slow and clumsy, but no help needed.
2 = Can cut most foods, although clumsy and slow; some help needed.
3 = Food must be cut by someone, but can still feed slowly.
4 = Needs to be fed.
10. Dressing
0 = Normal.
1 = Somewhat slow, but no help needed.
2 = Occasional assistance with buttoning, getting arms in sleeves.
3 = Considerable help required, but can do some things alone.
4 = Helpless.
11. Hygiene
0 = Normal.
1 = Somewhat slow, but no help needed.
2 = Needs help to shower or bathe; or very slow in hygienic care.
3 = Requires assistance for washing, brushing teeth, combing hair, going to bathroom.
4 = Foley catheter or other mechanical aids.
12. Turning in bed and adjusting bed clothes
0 = Normal.
1 = Somewhat slow and clumsy, but no help needed.
2 = Can turn alone or adjust sheets, but with great difficulty.
3 = Can initiate, but not turn or adjust sheets alone.
4 = Helpless.
13. Falling (unrelated to freezing)
0 = None.
1 = Rare falling.
2 = Occasionally falls, less than once per day.
3 = Falls an average of once daily.
4 = Falls more than once daily.
14. Freezing when walking
0 = None.
1 = Rare freezing when walking; may have starthesitation.
2 = Occasional freezing when walking.
3 = Frequent freezing. Occasionally falls from freezing.
4 = Frequent falls from freezing.
15. Walking
0 = Normal.
1 = Mild difficulty. May not swing arms or may tend to drag leg.
2 = Moderate difficulty, but requires little or no assistance.
3 = Severe disturbance of walking, requiring assistance.
4 = Cannot walk at all, even with assistance.
Version 1.0   14th June 2017
64

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
16. Tremor (Symptomatic complaint of tremor in any part of body.)
0 = Absent.
1 = Slight and infrequently present.
2 = Moderate; bothersome to patient.
3 = Severe; interferes with many activities.
4 = Marked; interferes with most activities.
17. Sensory complaints related to parkinsonism
0 = None.
1 = Occasionally has numbness, tingling, or mild aching.
2 = Frequently has numbness, tingling, or aching; not distressing.
3 = Frequent painful sensations.
4 = Excruciating pain.
III. MOTOR EXAMINATION
18. Speech
0 = Normal.
1 = Slight loss of expression, diction and/or volume.
2 = Monotone, slurred but understandable; moderately impaired.
3 = Marked impairment, difficult to understand.
4 = Unintelligible.
19. Facial Expression
0 = Normal.
1 = Minimal hypomimia, could be normal "Poker Face".
2 = Slight but definitely abnormal diminution of facial expression.
3 = Moderate hypomimia; lips parted some of the time.
4 = Masked or fixed facies with severe or complete loss of facial expression;
lips parted 1/4 inch or more.
20. Tremor at rest (head, upper and lower extremities)
0 = Absent.
1 = Slight and infrequently present.
2 = Mild in amplitude and persistent. Or moderate in amplitude, but only intermittently present.
3 = Moderate in amplitude and present most of the time.
4 = Marked in amplitude and present most of the time.
21. Action or Postural Tremor of hands
0 = Absent.
1 = Slight; present with action.
2 = Moderate in amplitude, present with action.
3 = Moderate in amplitude with posture holding as well as action.
4 = Marked in amplitude; interferes with feeding.
22. Rigidity (Judged on passive movement of major joints with patient relaxed in sitting position.
Cogwheeling to be ignored.)
0 = Absent.
1 = Slight or detectable only when activated by mirror or other movements.
2 = Mild to moderate.
3 = Marked, but full range of motion easily achieved.
4 = Severe, range of motion achieved with difficulty.
23. Finger Taps (Patient taps thumb with index finger in rapid succession.)
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.
4 = Can barely perform the task.
Version 1.0   14th June 2017
65

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
24. Hand Movements (Patient opens and closes hands in rapid succesion.)
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.
4 = Can barely perform the task.
25. Rapid Alternating Movements of Hands (Pronation-supination movements of hands, vertically and
horizontally, with as large an amplitude as possible, both hands simultaneously.)
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.
4 = Can barely perform the task.
26. Leg Agility (Patient taps heel on the ground in rapid succession picking up entire leg. Amplitude
should be at least 3 inches.)
0 = Normal.
1 = Mild slowing and/or reduction in amplitude.
2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.
3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.
4 = Can barely perform the task.
27. Arising from Chair
(Patient attempts to rise from a straightbacked chair, with arms folded across chest.)
0 = Normal.
1 = Slow; or may need more than one attempt.
2 = Pushes self up from arms of seat.
3 = Tends to fall back and may have to try more than one time, but can get up without help.
4 = Unable to arise without help.
28. Posture
0 = Normal erect.
1 = Not quite erect, slightly stooped posture; could be normal for older person.
2 = Moderately stooped posture, definitely abnormal; can be slightly leaning to one side.
3 = Severely stooped posture with kyphosis; can be moderately leaning to one side.
4 = Marked flexion with extreme abnormality of posture.
29. Gait
0 = Normal.
1 = Walks slowly, may shuffle with short steps, but no festination (hastening steps) or propulsion.
2 = Walks with difficulty, but requires little or no assistance; may have some festination, short steps,
or propulsion.
3 = Severe disturbance of gait, requiring assistance.
4 = Cannot walk at all, even with assistance.
30. Postural Stability (Response to sudden, strong posterior displacement produced by pull on shoulders
while patient erect with eyes open and feet slightly apart. Patient is prepared.)
0 = Normal.
1 = Retropulsion, but recovers unaided.
2 = Absence of postural response; would fall if not caught by examiner.
3 = Very unstable, tends to lose balance spontaneously.
4 = Unable to stand without assistance.
31. Body Bradykinesia and Hypokinesia (Combining slowness, hesitancy, decreased armswing, small
amplitude, and poverty of movement in general.)
0 = None.
1 = Minimal slowness, giving movement a deliberate character; could be normal for some persons.
Version 1.0   14th June 2017
66

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Possibly reduced amplitude.
2 = Mild degree of slowness and poverty of movement which is definitely abnormal.
Alternatively, some reduced amplitude.
3 = Moderate slowness, poverty or small amplitude of movement.
4 = Marked slowness, poverty or small amplitude of movement.
IV. COMPLICATIONS OF THERAPY (In the past week)
A. DYSKINESIAS
32. Duration: What proportion of the waking day are dyskinesias present?
(Historical information.)
0 = None
1 = 1-25% of day.
2 = 26-50% of day.
3 = 51-75% of day.
4 = 76-100% of day.
33. Disability: How disabling are the dyskinesias?
(Historical information; may be modified by office examination.)
0 = Not disabling.
1 = Mildly disabling.
2 = Moderately disabling.
3 = Severely disabling.
4 = Completely disabled.
34. Painful Dyskinesias: How painful are the dyskinesias?
0 = No painful dyskinesias.
1 = Slight.
2 = Moderate.
3 = Severe.
4 = Marked.
35. Presence of Early Morning Dystonia (Historical information.)
0 = No
1 = Yes
B. CLINICAL FLUCTUATIONS
36. Are "off" periods predictable?
0 = No
1 = Yes
37. Are "off" periods unpredictable?
0 = No
1 = Yes
38. Do "off" periods come on suddenly, within a few seconds?
0 = No
1 = Yes
39. What proportion of the waking day is the patient "off" on average?
0 = None
1 = 1-25% of day.
2 = 26-50% of day.
3 = 51-75% of day.
4 = 76-100% of day.
C. OTHER COMPLICATIONS
40. Does the patient have anorexia, nausea, or vomiting?
0 = No
Version 1.0   14th June 2017
67

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
1 = Yes
41. Any sleep disturbances, such as insomnia or hypersomnolence?
0 = No
1 = Yes
42. Does the patient have symptomatic orthostasis?
(Record the patient's blood pressure, height and weight on the scoring form)
0 = No
1 = Yes
V. MODIFIED HOEHN AND YAHR STAGING
STAGE 0 = No signs of disease.
STAGE 1 = Unilateral disease.
STAGE 1.5 = Unilateral plus axial involvement.
STAGE 2 = Bilateral disease, without impairment of balance.
STAGE 2.5 = Mild bilateral disease, with recovery on pull test.
STAGE 3 = Mild to moderate bilateral disease; some postural instability; physically independent.
STAGE 4 = Severe disability; still able to walk or stand unassisted.
STAGE 5 = Wheelchair bound or bedridden unless aided.
Version 1.0   14th June 2017
68

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
C.
Mini-Mental State Examination (MMSE)
Patient’s Name:_____________________________________ Date: 
_________
Instructions: Ask the questions in the order listed. Score one point for each correct 
response within each question or activity.
 
Maximum
Score
Patient’s
Score
 
Questions
5
 
“What is the year? Season? Date? Day of the week? Month?”
5
 
“Where are we now: State? County? Town/city? Hospital? Floor?”
 
 
3
 
The examiner names three unrelated objects clearly and slowly, then
asks the patient to name all three of them. The patient’s response is
used for scoring. The examiner repeats them until patient learns all of
them, if possible. Number of trials:
 
 
5
 
“I would like you to count backward from 100 by sevens.” (93, 86, 79,
72, 65, …) Stop after five answers.
Alternative: “Spell WORLD backwards.” (D-L-R-O-W)
 
3
 
“Earlier I told you the names of three things. Can you tell me what those
were?”
 
2
 
Show the patient two simple objects, such as a wristwatch and a pencil,
and ask the patient to name them.
1
 
“Repeat the phrase: ‘No ifs, ands, or buts.’”
 
3
 
“Take the paper in your right hand, fold it in half, and put it on the floor.”
(The examiner gives the patient a piece of blank paper.)
 
1
 
“Please read this and do what it says.” (Written instruction is “Close your
eyes.”)
 
1
 
“Make up and write a sentence about anything.” (This sentence must
contain a noun and a verb.)
 
 
1
 
“Please copy this picture.” (The examiner gives the patient a blank
piece of paper and asks him/her to draw the symbol below. All 10
angles must be present and two must intersect.)
30
 
TOTAL
Version 1.0   14th June 2017
70

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
Instructions for administration and scoring of the MMSE
Orientation (10 points):
•
Ask for the date. Then specifically ask for parts omitted (e.g., "Can you also tell
me what season it is?"). One point for each correct answer.
•
Ask in turn, "Can you tell me the name of this hospital (town, county, etc.)?"
One point for each correct answer.
Registration (3 points):
•
Say the names of three unrelated objects clearly and slowly, allowing
approximately one second for each. After you have said all three, ask the patient to
repeat them. The number of objects the patient names correctly upon the first
repetition determines the score (0-3). If the patient does not repeat all three objects
the first time, continue saying the names until the patient is able to repeat all three
items, up to six trials. Record the number of trials it takes for the patient to learn
the words. If the patient does not eventually learn all three, recall cannot be
meaningfully tested.
•
After completing this task, tell the patient, "Try to remember the words, as I
will ask for them in a little while."
Attention and Calculation (5 points):
•
Ask the patient to begin with 100 and count backward by sevens. Stop after five
subtractions (93, 86, 79, 72, 65). Score the total number of correct answers.
•
If the patient cannot or will not perform the subtraction task, ask the patient to
spell the word "world" backwards. The score is the number of letters in correct
order (e.g., dlrow=5, dlorw=3).
Recall (3 points):
•
Ask the patient if he or she can recall the three words you previously
asked him or her to remember. Score the total number of correct
answers (0-3).
Language and Praxis (9 points):
•
Naming: Show the patient a wrist watch and ask the patient what it is. Repeat
with a pencil. Score one point for each correct naming (0-2).
•
Repetition: Ask the patient to repeat the sentence after you ("No ifs, ands, or
buts."). Allow only one trial. Score 0 or 1.
•
3-Stage Command: Give the patient a piece of blank paper and say, "Take this
paper in your right hand, fold it in half, and put it on the floor." Score one point
for each part of the command correctly executed.
•
Reading: On a blank piece of paper print the sentence, "Close your eyes," in
letters large enough for the patient to see clearly. Ask the patient to read the
Version 1.0   14th June 2017
71

Duodopa® (Levodopa-Carbidopa Intestinal Gel –LCIG-)
P16-831 Protocol
sentence and do what it says. Score one point only if the patient actually closes
his or her eyes. This is not a test of memory, so you may prompt the patient to
"do what it says" after the patient reads the sentence.
•
Writing: Give the patient a blank piece of paper and ask him or her to write a
sentence for you. Do not dictate a sentence; it should be written spontaneously.
The sentence must contain a subject and a verb and make sense. Correct
grammar and punctuation are not necessary.
•
Copying: Show the patient the picture of two intersecting pentagons and ask the
patient to copy the figure exactly as it is. All ten angles must be present and two
must intersect to score one point. Ignore tremor and rotation.
Interpretation of the MMSE
Method
Score
Interpretation
Single Cutoff
<24
Abnormal
Range
<21
 
>25
Increased odds of dementia
 
Decreased odds of dementia
Education
21
Abnormal for 8th grade education
<23
Abnormal for high school education
<24
Abnormal for college education
Severity
24-30
No cognitive impairment
18-23
Mild cognitive impairment
0-17
Severe cognitive impairment
Sources:
•
Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for
the mini-mental state examination by age and educational level. JAMA.
1993;269(18):2386-2391.
•
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state": a practical method for
grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-
198.
•
Rovner BW, Folstein MF. Mini-mental state exam in clinical practice. Hosp Pract.
1987;22(1A):99, 103, 106, 110.
•
Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J
Am Geriatr Soc.
1992;40(9):922-935.
Version 1.0   14th June 2017
72