Treatment in Advanced Parkinson's Disease: Continuous Intrajejunal Levodopa INfusion VErsus Deep Brain STimulation
Phase: PHASE4
Conditions: Parkinson's Disease
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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The INVEST study 
Treatment in advanced Parkinson’s disease: continuous intrajejunal 
levodopa INfusion VErsus deep brain STimulation. 
 
 
 
 
 
 
October 2019 
Amsterdam UMC location AMC, Amsterdam 
University of Amsterdam 
 

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PROTOCOL TITLE The INVEST study. Treatment in advanced Parkinson’s disease: 
continuous intrajejunal levodopa INfusion VErsus deep brain STimulation. 
 
Protocol ID 
NL51240.018.14   
Short title 
INVEST (Infusion Versus STimulation) study 
EudraCT number  
2014.001501.32 
Version 
7 
Date 
23-10-2019 
Coordinating 
investigator/project leader 
dr. J.M. Dijk 
Principal investigator 
dr. J.M. Dijk  
Amsterdam UMC location AMC 
Department of Neurology  
PO box 22660, 1100 DD Amsterdam 
j.m.dijk@amsterdamumc.nl 
Executing investigator 
drs. D. van Poppelen 
Amsterdam UMC location AMC 
Department of Neurology  
PO box 22660, 1100 DD Amsterdam 
d.vanpoppelen@amsterdamumcnl 
Participating centres 
see appendix 12.1 for 
investigators on site 
 
Amsterdam UMC location AMC 
Amsterdam UMC location VUMC 
Bronovo Ziekenhuis 
Canisius Wilhelmina Ziekenhuis 
Flevoziekenhuis 
HagaZiekenhuis 
Maastricht UMC+ 
Onze Lieve Vrouwe Gasthuis 
Radboud UMC 

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Reinier de Graaf Gasthuis 
Spaarne Gasthuis  
Zuwe Hofpoort Ziekenhuis 
Zuyderland Medisch Centrum 
Sponsor 
dr. J.M. Dijk 
Subsidising party 
ZonMW. Project number 837002509 
Independent expert  
dr. P.J. Nederkoorn 
Amsterdam UMC location AMC 
Department of Neurology  
PO box 22660, 1100 DD Amsterdam 
p.j.nederkoorn@amc.uva.nl 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. dr. B.M.J. Uitdehaag 
 
 
 
Project leader: 
Dr. J.M. Dijk, neurologist 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................12 
3. 
STUDY DESIGN ...........................................................................................................13 
4. 
STUDY POPULATION ..................................................................................................14 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................16 
4.4 
Sample size calculation ..........................................................................................16 
5. 
TREATMENT OF SUBJECTS .......................................................................................19 
5.1 
Investigational product/treatment ............................................................................19 
5.2 
Use of co-intervention ............................................................................................20 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................21 
6.1 
Name and description of investigational product(s) ................................................21 
6.2 
Summary of findings from non-clinical studies ........................................................21 
6.3 
Summary of findings from clinical studies ...............................................................21 
6.4 
Summary of known and potential risks and benefits ...............................................21 
6.5 
Description and justification of route of administration and dosage .........................21 
6.6 
Dosages, dosage modifications and method of administration ...............................21 
7. 
METHODS ....................................................................................................................23 
7.1 
Study parameters/endpoints ...................................................................................23 
7.1.1 
Main study parameter/endpoint .......................................................................23 
7.1.2 
Secondary study parameters/endpoints ..........................................................23 
7.1.3 
Other study parameters ...................................................................................23 
7.2 
Randomisation, blinding and treatment allocation ..................................................23 
7.3 
Study procedures ...................................................................................................24 
7.4 
Withdrawal of individual subjects ............................................................................26 
7.5 
Follow-up of subjects withdrawn from treatment .....................................................27 
7.6 
Premature termination of the study .........................................................................27 
8. 
SAFETY REPORTING ..................................................................................................28 
8.1 
Temporary half for reasons of subject safety ..........................................................28 
8.2 
AEs, SAEs and SUSARs ........................................................................................28 
8.2.1 
Adverse events (AEs) ......................................................................................28 
8.2.2 
Serious adverse events (SAEs) .......................................................................28 
8.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................30 
8.3 
Annual safety report ...............................................................................................31 
8.4 
Follow-up of adverse events ...................................................................................31 
8.5 
Pregnancy ..............................................................................................................31 
8.6 
Data Safety Monitoring Board (DSMB) / Safety Committee] ...................................31 
8.7 
Primary study parameter(s) ....................................................................................32 
8.8 
Secondary study parameter(s) ...............................................................................32 
8.9 
Interim analysis (if applicable) ................................................................................33 

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9. 
ETHICAL CONSIDERATIONS ......................................................................................34 
9.1 
Regulation statement .............................................................................................34 
9.2 
Recruitment and consent........................................................................................34 
9.3 
Benefits and risks assessment, group relatedness .................................................35 
9.4 
Compensation for injury .........................................................................................35 
9.5 
Incentives (if applicable) .........................................................................................36 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................37 
10.1 
Handling and storage of data and documents ........................................................37 
10.2 
Monitoring ..............................................................................................................37 
10.3 
Amendments ..........................................................................................................37 
10.4 
Annual progress report ...........................................................................................38 
10.5 
End of study report .................................................................................................38 
10.6 
Public disclosure and publication policy ..................................................................38 
11. 
STRUCTURED RISK ANALYSIS...............................................................................39 
11.1 
Potential issues of concern .....................................................................................39 
11.2 
Synthesis ...............................................................................................................39 
12. 
APPENDICES............................................................................................................40 
12.1 
Contributing centres ...............................................................................................40 
12.2 
Summary of Product Characteristics (SPC) of Duodopa ........................................41 
12.3 
Motivation for outcome measures ...........................................................................42 
12.4 
Assessment schedules ...........................................................................................43 
12.5 
Cost Effectiveness analysis (CEA) .........................................................................45 
12.6 
Patient outcome analysis........................................................................................47 
13. 
REFERENCES ..........................................................................................................48 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee 
(In Dutch, ABR = Algemene Beoordeling en Registratie) 
aPTT 
activated partial thromboplastin time 
AE 
Adverse Event 
ALDS 
AMC Linear Disability Score 
AMC 
Academic Medical Center 
AR 
Adverse Reaction 
CA 
Competent Authority 
CAI 
Continuous subcutaneous Apomorphine Infusion 
CBO 
Centraal BegeleidingsOrgaan 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CDRS 
Clinical Dyskinesia Rating Scale  
CEA 
Cost Effectiveness analysis (CEA) 
CLI 
Continuous intrajejunal Levodopa Infusion 
CRF 
Case Report Form 
CRU 
AMC Clinic Research Unit 
CT 
Computed Tomography 
CV 
Curriculum Vitae 
DBS 
Deep Brain Stimulation 
DSMB 
Data Safety Monitoring Board 
EKG 
Electocardiogram 
EQ-5D 
Euro-Qol 5D 
EU 
European Union 
FDA 
21CFR  
US Food and Drug Administration Code of Federal Regulations Title 21 
EudraCT 
European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
iMCQ 
Institute for Medical Technology Assessment Medical Consumption 
Questionnaire  
IMP 
Investigational Medicinal Product  

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IMPD 
Investigational Medicinal Product Dossier  
INVEST 
Infusion Versus Stimulation 
iPCQ 
Institute for Medical Technology Assessment Productivity Cost 
Questionnaire  
MDS-
UPDRS 
Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
MINI 
Mini-International Neuropsychiatric Interview 
 
 
MRI 
Magnetic Resonance Imaging 
NFU 
Nederlandse Federatie van Universitaire Medische Centra 
NSTAPS 
The Netherlands SubThalamic and Pallidal Stimulation 
PD 
Parkinson’s Disease 
PD-CRS 
Parkinson’s Disease Cognitive Rating Scale 
PDQ-39 
The 39-Item Parkinson's Disease Questionnaire  
PEG 
Percutaneous Endoscopic Gastrostomy 
PIN 
Patient Identification Number 
PT 
Prothrombin Time 
PROAPD 
Patient-reported outcome tool for advanced Parkinson’s disease  
QALY 
Quality Adjusted Life Year 
RCT 
Randomized Controlled Trail 
RvZ 
Raad voor de Volksgezondheid 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie 
IB1-tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
STN 
Subthalamic Nucleus 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming 
Persoonsgevens) 
WTP 
Willingness-to-pay 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
Rationale: Both Continuous intrajejunal Levodopa Infusion (CLI) and Deep Brain Stimulation 
(DBS) are accepted therapies for the treatment of advanced Parkinson’s disease (PD). 
Neurologists and patients tend to prefer the more expensive CLI although a scientific 
rationale is lacking. To determine the optimal treatment in advanced PD, a comparative study 
of CLI and DBS is warranted. 
Hypothesis: We hypothesize that CLI is a more expensive therapy in advanced PD than 
DBS and that the surplus in costs is not cost-effective with regard to benefits for the patient 
and caregivers in quality of life, PD symptoms and adverse events.  
Objective: To realize a cost-effective treatment strategy in advanced PD.  
Study design: Prospective, randomized, open label multicentre trial, with two additional 
observational patient preference treatment arms (“patient preference randomized trial”). 
Study population: Patients with PD who, despite optimal pharmacological treatment, have 
severe response fluctuations, dyskinesias, painful dystonia, or bradykinesia. A total of 66 
patients will be randomized, at least120 patients will be included in the patient preference 
arms. 
Intervention: Patients will be randomized to DBS or CLI. For DBS treatment, 2 electrodes 
will be implanted in the brain. The electrodes are connected to an implanted pulse generator, 
which will be placed subcutaneously in the subclavian area. For CLI treatment, a tube will be 
placed in the jejunum via a percutaneous endoscopic gastrostomy (PEG). This tube is 
connected to an external pump that delivers the levodopa-gel. 
Main study parameters: There are 8 specified assessment visits for the patients in the 
randomized trial: at baseline, and 1 week, 3, 6, 9, 12, 24 and 36 months after start of the 
study treatment. The primary health economic outcomes are the costs per unit on the PDQ-
39 and the costs per QALY for the cost-effectiveness and cost-utility analyses, respectively. 
The EQ-5D will be applied as the utility measure. Among the secondary outcomes are 
neurological impairments, functional health, care use and perceptions of patients and 
neurologists regarding both treatments. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The study investigates the cost-effectiveness and cost-utility comparing 
CLI and DBS. Both treatments are currently available for advanced PD and both have a 
small risk of severe side effects. The surplus in burden of study participation compared to the 
regular treatment consists of a more detailed assessment procedure. The additional time for 
these extra assessments — consisting of questionnaires and motor symptom assessments 
— is approximately 15 hours, including time to travel. Besides this small burden the study 
has no additional risk compared to standard practice, which constitutes a negligible risk 

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according to the NFU (Nederlandse Federatie van Universitaire Medische Centra) criteria for 
human research. 
 
1.  INTRODUCTION AND RATIONALE 
Parkinson’s disease (PD) is a neurodegenerative disease affecting the motor, autonomic, 
cognitive, and sensory systems. It is a disease of the elderly: above the age of 55 years, the 
prevalence of PD is 1.4%.[1] In 2011, almost 60.000 patients in the Netherlands were 
estimated to have PD and due to ageing of the population an increase of at least 50% is 
expected in the following years.[2] PD is one of the diseases causing the largest reduction in 
quality of life and social functioning and the ability to work are impaired. 
The core symptoms of PD are caused by the degeneration of dopamine producing neurons. 
At present there is no cure for PD, but several symptomatic therapies are available that 
mainly act upon the motor symptoms. Most of these (i.e., tremor, rigidity and bradykinesia) 
initially respond well to oral dopamine replacement although dyskinesias frequently occur 
after a variable period. Patients with advanced PD frequently show rapid and seemingly 
unpredictable swings between mobility, often with dyskinesias (ON-phase), and immobility 
(OFF-phase).[3] In the Netherlands, the prevailing treatment options for these patients are 
Deep Brain Stimulation (DBS) and Continuous intrajejunal Levodopa Infusion (CLI).[4] 
Continuous apomorphine infusion (CAI) is gaining more ground as another treatment option, 
since this treatment was researched in a recent double blind randomised controlled trial.[5] 
 
For DBS, a neurosurgeon places two electrodes in the brain. These are connected to an 
implantable pulse generator. Patients continue with PD medications, though often at a lower 
dose.  
For CLI, a gastroenterologist places a tube in the jejunum, which is connected to a portable 
pump. A levodopa-gel is continuously administered through the tube. In general, patients 
with CLI may stop other PD medications. Similar to DBS treatment, patients are hospitalized 
for placement of the tube and for the start of the levodopa-gel treatment. In both treatments, 
patients regularly visit the outpatient clinic to adjust the treatment.  
Another treatment option for patients with advanced PD is Continuous subcutaneous 
Apomorphine Infusion (CAI). In the Netherlands CAI is used in a smaller number of patients. 
CAI is not included in this research protocol, because at start of this trial, the evidence for 
effectiveness of CAI was of poor quality. Besides, CAI is slightly more expensive than DBS. 
A study that directly compares all three treatments is not feasible because of the large 
sample size needed. 
Both treatment with DBS and CLI is expensive. We estimate that DBS equipment and 
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€45,000 per patient/year. In addition, patients need surgery and they frequently visit the 
clinic. In a recent Spanish study the mean cumulative 5-year cost per patient (including the 
surgery) was estimated € 88,014 for DBS and € 233,986 for CLI. [6] 
 
Several level I studies have shown that DBS is efficacious for the treatment of PD motor 
symptoms: it reduces dyskinesias and motor fluctuations.[7] CLI reduces off-time and is 
effective for the treatment of motor fluctuations and dyskinesias as was shown in a few small 
and one larger level I trial. Both therapies significantly improve quality of life.[7-13] No head-
to-head comparison of DBS and CLI has been performed, but when comparing individual 
studies, the effects on quality of life are similar.[8, 13] Little is known about comparative 
adverse-effects profiles of the therapies. One retrospective study suggests a higher rate of 
complications in CLI.[14]  
 
The lack of comparative knowledge is reflected in the current CBO-guideline for PD (2010), 
which states no preference for one of the therapies.[4] Both DBS and CLI are available in the 
Netherlands and both are covered by the basic health insurance. After the introduction of CLI 
in 2007, the number of patients with PD receiving the traditionally standard treatment DBS 
initially slightly decreased, while the number of patients receiving CLI has increased, 
resulting in an approximately equal number of yearly DBS and CLI procedures in the 
Netherlands at the moment (80 each). [15] Currently, an estimated 600 PD patients have 
DBS and 300 patients are treated with CLI in the Netherlands. At present, there is unwanted 
variation in medical practice. Surveys we performed showed that out of 287 Dutch 
neurologists (response 50.5%), 45% prefers CLI and 35% prefers DBS. In 62 PD patients 
from a regional branch of the Dutch Parkinson Association only treated with oral medication, 
40% prefers CLI, against 9% preferring DBS and 51% without preference.  
That both patients and neurologists tend to prefer CLI over the traditionally standard 
treatment DBS, is of interest considering the lower level of evidence of CLI, but also given 
the fact that CLI probably is much more expensive than DBS.  
 
In this comparative study between DBS and CLI we will assess the cost-effectiveness of both 
treatment options in advanced PD. Results of the INVEST study will probably lead to an 
unambiguous practice guideline. The resulting more efficient care may facilitate treatment 
with DBS in the more early stage of the disease process.[12] 
 

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2. OBJECTIVES 
 
2.1 Primary Objective 
To realize an efficient allocation of resources to the available treatment options in advanced 
PD, while guaranteeing the highest standard of care. 
 
For the primary objective the following research questions will be answered:  
1. What are, in the Netherlands, the direct and indirect costs and benefits of CLI and DBS as 
the two prevailing treatment options for advanced PD? 
2. Is CLI cost-effective in advanced PD when compared to DBS? 
3. With regard to the implementation, what are the perceptions about the two therapies in 
advanced PD in patients and neurologists and do they correspond to the actual figures on 
burden of the procedure and care, the effects, adverse events and costs? 
 
2.2 Secondary Objectives 
Secondary objectives are to compare motor and non-motor symptoms, quality of life, and 
daily functioning, adverse effects and complications between treatment with DBS and CLI.  
 
 

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3. STUDY DESIGN 
A prospective open label multi-centre randomized controlled trail (RCT) will be performed, 
with two additional patient preference arms (“patient preference randomized trial”).  
Patients who do not want to be randomized for treatment with one of the available therapies, 
will be asked to participate in the patient preference observational study. All patients will 
undergo a baseline evaluation and an assessment at the end of the 12-month follow-up (see 
figure 1 on page 15). A prolonged follow-up of 24 and 36 months will be evaluated too. A 
total of 66 patients will be included in the RCT and at least 120 patients are expected to take 
part in the patient preference part of the study.  
For patients that do not want to take part in the patient preference randomized trial, the 
treating neurologist will be asked to fill in an anonymous questionnaire assessing general 
information in terms of age, sex, medication, age of onset PD, duration of PD, comorbidities 
and therapy of choice.  
 
Because DBS and CLI are invasive treatments and both procedures have a (small) risk for 
irreversible and severe adverse events, it is not ethical to perform additional sham 
procedures. Therefore it is not possible to blind the patient for treatment assignment. As the 
primary health economic outcome and the primary clinical outcome are both based on 
patient-reported perceived quality of life measure (PDQ-39), a blinded endpoint  assessment 
(PROBE-design)  is not possible. 
 
Rationale for the design 
The RCT design in combination with an observational patient preference study was chosen 
because the studied therapies are available and differ largely. Currently, patients and 
neurologists together decide on what therapy to choose. Both patients and treating 
neurologists seem to have specific perceptions about the therapies. Consequently, the 
proportion of patients that is willing to be randomized between the two available treatments 
may be relatively small. This patient selection may restrict the generalization of the RCT 
results. Therefore, patients who are not willing to be randomized will be asked to take part in 
the patient preference observational study. These patients are allowed to receive their 
desired treatment without randomization and will be studied with respect to their baseline 
characteristics, primary clinical outcome and adverse events of the treatment. If the 
randomized patients resemble the non-randomized patients the RCT-results reflect a more 
accurate estimate of the treatment benefits and greater evidence of its external validity.

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Figure 1, flowchart 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Research population and source population 
Patients with advanced PD who are eligible for treatment with both DBS and CLI. Adult 
patients will be recruited from academic and non-academic hospitals. 
 
Feasibility  
Currently, in the Netherlands, each year approximately 140 patients are eligible for 
treatment with DBS and CLI (all 80 patients yearly treated with DBS and approximately 
80% of 80 patients yearly treated with CLI).  
Approximately 160 are treated with DBS or CLI in the Netherlands yearly. We estimate 
that 140 patients will be eligible for the study and that 110 are initially treated in one of the 
participating centres. With a study duration of 33 months 302 patients will be eligible. This 
implies that a total of 66 patients (22% of eligible patients) will need to be randomized to 
assess cost-effectiveness of the treatments. This is a realistic goal because in the latest 
study in the same patient population, 58% of the eligible patients were recruited.[11] 
 
For the two patient preference arms, we estimate that up to 180 patients will take part (i.e. 
60% of the eligible population). It is our experience, from discussions with representatives 
of the Parkinson’s disease association and in the outpatient clinic, that patients consider it 
important that more information on treatment of advanced PD becomes available. 
Therefore, we think this is a realistic estimation. The burden of cooperation is low for the 
patient, especially since visits for the study will be combined with visits to the outpatient 
clinic for regular care or will be performed at home. 
 
Characteristics of study population 
PD is a disease of the elderly. We expect the population will be similar to the NSTAPS 
study, a study that was recently performed in the Academic Medical Center, comparing 
treatment with DBS in two different targets in the brain. In this study, the mean age was 
approximately 60 years, with a mean age of onset of PD of 49 years. In the NSTAPS 
study about 69% of the patients was male.[11] 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria:  
Age > 18 years 

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• idiopathic PD with bradykinesia and at least two of the following signs; resting tremor, 
rigidity, and asymmetry; 
• despite optimal pharmacological treatment, at least one of the following symptoms: 
severe response fluctuations, dyskinesias, painful dystonia or bradykinesia; 
• a life expectancy of at least two years. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
• legally incompetent adults 
• previous PD-neurosurgery (e.g., DBS, pallidotomy, thalamotomy); 
• previous CLI (through a PEG-tube or Nasal Jejunal tube); 
• contraindications for DBS surgery, such as a physical disorder making surgery 
hazardous; 
• contraindications for PEG surgery such as interposed organs, ascites and 
oesophagogastric varices, or for Duodopa; 
• Hoehn and Yahr stage 5 at the best moment during the day; 
• other, severely disabling condition 
• dementia or indication for severe cognitive impairment, such as PD-CRS <65 
• psychosis; 
• current depression; 
• pregnancy, breastfeeding, and women of child bearing age not using a reliable method 
of contraception; 
• no written informed consent; 
• age below 18 years; 
 
4.4 Sample size calculation 
RCT 
The primary objective of the study is to realize an efficient allocation of resources to the 
available treatment options in advanced PD. For this, primarily an economic evaluation will 
be carried out and the sample size has been calculated accordingly. Society’s willingness-to-
pay (WTP) per Quality Adjusted Life Year (QALY) may be indicative of whether or not CLI is 
affordable compared to DBS. The Dutch Raad voor de Volksgezondheid (RvZ) reported a 
value of €80,000 per additional QALY in 2006 as a potential upper limit of affordability. 
Explicitly, the figure is reported by the RvZ as a potential, but also unofficial limit: it should 

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not be taken as a definite one. Other arguments based on patient preference or access to 
health care should be taken into account as well. Considering that CLI may be a less 
invasive intervention and access to health care is easier to facilitate when two interventions 
can be provided, a more lenient upper limit for the extra societal costs per additional QALY 
may be appropriate here. We propose a sample size calculation based on a WTP per 
additional QALY of €120,000 (50% above the RvZ figure). Based on the net health benefit 
formula suggesting that differences in QALYs between the interventions should be larger 
than the difference in costs (i.e., €34,174 a year) divided by the maximum WTP (i.e., 
€120,000 per QALY) in order for one intervention to be accepted as more efficient than 
another intervention, CLI treatment should at least outperform DBS treatment by 0.2847 
QALY per year. Based on literature data with comparable costs estimates, [6] we anticipate 
standard deviations (SD) for QALYs up to 0.35 and for total costs up to €10,000 (factoring in 
a 12-month follow-up and non-responders).  
To achieve 80% power and given a two-sided significance level of 0.05, up to 26 patients per 
group (or 52 in total) are needed to detect a difference of at least 0.2847 QALY for WTP-
values up to €120,000 and a worst case scenario of zero correlation between costs and 
clinical effect, using a two-group t-test. Accounting for a possible dropout of 20%, we will 
randomize 66 patients (33 per group). With this sample size and given the same test 
conditions (power, type-I error rate, test chosen, drop-out rate) we are also able to detect a 
difference in mean PDQ-39 scores between both groups of 11.9, assuming an expected 
mean score of 32 in the DBS group and a standard deviation of 15. 
 
Motivation for standard deviations for QALY 
Literature data [8-10] show that the standard deviation for PDQ-39 scores from operated PD 
patients equals 15 points and that a 4 to 5 points difference is associated with a QALY 
difference of approximately 0.1,[16] suggesting a standard deviation for QALYs of up to 0.35. 
 
Patient preference trial 
We (conservatively) estimate that during the inclusion period a total of 180 patients (60% of 
the eligible patients) may decline to participate in the RCT, but are willing to take part in the 
preference observational study. Based on our clinical experience it is expected that 60% of 
these patients (n=108) prefers DBS, against 40% (n=72) preferring CLI. 
 
When comparing the effect of DBS treatment of patients who express a preference for that 
treatment with the effect of DBS treatment in the randomised patients, and given the same 
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mean PDQ-39 scores between both groups of 8,4, assuming an expected mean score of 32 
in the randomized DBS group and a standard deviation of 15. 
In case only 120 patients (40% of the eligible patients) agree to take part in the preference 
observational study, we are able to detect a difference in mean PDQ-39 scores between both 
DBS groups of 8,9. 
 
When comparing the effect of CLI treatment for patients who express a preference for that 
treatment with the effect of CLI treatment in the randomised patients, and given the same 
test conditions (power, type-I error rate, chosen test) we are able to detect a difference in 
mean PDQ-39 scores between both groups of 8,9, assuming an expected mean score of 
43,9 in the randomized CLI group and a standard deviation of 15. In case only 120 patients 
(40% of the eligible patients) agree to take part in the preference observational study, we are 
able to detect a difference in mean PDQ-39 scores between both CLI groups of 9,6. 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
CLI and DBS are both complex treatments and are therefore performed by teams that 
consist of various specialties (e.g. neurologist, neurosurgeon, gastroenterologist, and 
specialized nurses). In the Netherlands, 6 centres are permitted to perform DBS. Three of 
these also offer CLI, but in a much smaller number. CLI is performed in approximately 45 
centres. For the study, CLI and DBS treatments should be optimally performed, i.e. by the 
best-trained teams. It is inevitable that the centres that perform the treatments at present 
perform the study-treatments as well. This implies that CLI and DBS will be carried-out in 
different centres. An advantage of this (Dutch) situation is that the study design closely 
resembles the current clinical practice, and as such the study results will be highly 
externally valid. 
 
DBS treatment (Medtronic, Minneapolis, MN, USA)  
Treatment is in accordance with the usual care regarding this procedure. For DBS, a 
neurosurgeon places two electrodes in the brain. These are connected to an implantable 
pulse generator. Patients are on average 4 days hospitalized. Patients do not receive PD 
drugs on the day of surgery until the end of the procedure. A stereotactic technique will be 
employed for implantation with the Leksell stereotactic frame (Elekta, Stockholm, Sweden) 
and guided by MRI. For this part of the surgery, patients will have local or general 
anaesthesia, both methods are possible in usual care and the surgeon will decide the 
method with the patient. The decision for electrode placement is based on MRI, 
microelectrode recordings and macro-electrode stimulation effects. A four contact 
electrode will be implanted in the subthalamic nucleus (STN). Subsequently, patients will 
have a second surgery under general anaesthesia to implant the pulse generator 
(ActivaPC or ActivaSC), subcutaneously in the subclavian area. The electrodes are 
connected to the pulse generator. During the course of the study, changes in drug 
treatment are allowed. Patients will regularly visit the outpatient clinic to adjust stimulation 
parameters and PD medication while assessing the interaction between both treatments. 
 
CLI treatment (Duodopa, Abbott, Abbott Park, IL, USA) 
Treatment is in accordance with the usual care regarding this procedure. In CLI, a 
levodopa-gel is continuously administered through a tube in the jejunum. The CLI-gel is 
dispensed into cassettes connected to an ambulatory programmable pump that delivers 
the suspension. One cassette supplies 100 ml gel containing 2000 mg levodopa and 500 
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The pump and cassette weight approximately 0.5 kg. The initiation and dose adjustments 
of CLI require 5 to 12 days of hospitalization. In some centres,  a temporary nasoduodenal 
tube is used to find out if the patient responds favourably to continuous levodopa infusion 
on day 1 to 3. On day 1 or 4 (depending on whether a temporary nasoduodenal tube is 
used first), a gastroenterologist endoscopically places a PEG tube in the stomach with an 
extension tube clipped in the jejunum using local anaesthetic and sedation with a short 
acting benzodiazepine. The tube is subsequently connected to the pump. Thereafter, CLI 
will immediately be continued and subsequently adjusted within the following days of 
inpatient stay. On day 5 to 12, the patient will be discharged. Patients will regularly visit 
the outpatient clinic to adjust the dose. Most patients use the pump only during daytime. 
 
5.2 Use of co-intervention  
The use of oral co-medication is allowed, as in regular daily practice. The treating 
neurologist supervises any changes in medication. The main motivation for this approach 
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6. INVESTIGATIONAL PRODUCT  
The medicinal product under investigation in this study is Duodopa, an intestinal gel 
containing levodopa and carbidopa, produced by Abbott pharmaceuticals. The information 
being referred to in the next section is derived from the Summary of Product Characteristics 
(SPC) of Duodopa, which is available in appendix 13.2 and D2 SPC Duodopa. The product 
will be used according to market authorization. The study does not contain any investigation 
of unauthorized use of Duodopa. 
  
6.1 Name and description of investigational product(s) 
For a description of Duodopa intestinal gel, see page 1-3, section 1 to 4.2 of the SPC 
(appendix 13.2). 
 
6.2 Summary of findings from non-clinical studies 
For a summary of findings from non-clinical studies on Duodopa intestinal gel, see page 15, 
section 5.3 of the SPC (appendix 13.2). 
 
6.3 Summary of findings from clinical studies 
Four RCTs [13, 17-19] and a number of lower quality studies evaluated CLI by comparison 
with best oral medical treatment. Overall, CLI showed improvements regarding PD motor 
symptoms (UPDRS motor examination), ON-phase time, and functional health. Two CLI 
RCT’s  also assessed patient-reported perceived quality of life with the PDQ-39, which 
improved in correlation with motor symptoms and functional health. [13, 18] 
 
6.4 Summary of known and potential risks and benefits 
For a summary of potential undesirable effects of Duodopa intestinal gel, we refer to page 3-
11, section 4.3 to 4.9 of the SPC (appendix 13.2). 
 
6.5 Description and justification of route of administration and dosage 
For a description of the pharmacological properties both pharmacodynamics and 
pharmacokinetics see page 8 and 9, section 5.1 and 5.2 of the SPC (appendix 13.2). 
 
6.6 Dosages, dosage modifications and method of administration 
For a description of posology and the method of administration see page 2 to 3, section 4.2, 
of the SPC (appendix 13.2). 

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The total dose/day of Duodopa is composed of three individually adjusted doses: the 
morning bolus dose, the continuous maintenance dose and extra bolus doses. 
Morning dose: The morning bolus dose is administered by the pump to rapidly achieve the 
therapeutic dose level (within 10-30 minutes). The dose is based on the patient’s previous 
morning intake of levodopa and the volume to fill the tubing. The total morning dose is 
usually 5-10 ml, corresponding to 100-200 mg levodopa. The total morning dose should not 
exceed 15 ml (300 mg levodopa). 
Continuous maintenance dose: The maintenance dose is adjustable in steps of 2 mg/hour 
(0.1 ml/hour). The dose is calculated according to the patient’s previous daily intake of 
levodopa. When supplementary medicines are discontinued the Duodopa dose should be 
adjusted. The continuous maintenance dose is adjusted individually. It should be kept within 
a range of 1-10 ml/hour (20-200 mg levodopa/hour) and is usually 2-6 ml/hour (40-120 mg 
levodopa/hour). In exceptional cases a higher dose may be needed. 
Extra bolus doses: To be given as required if the patient becomes hypokinetic during the 
day. The extra dose has to be adjusted individually, normally 0.5-2.0 ml. In rare cases a 
higher dose may be needed. If the need for extra bolus doses exceeds 5 per day the 
maintenance dose should be increased. 
After the initial dose setting, fine adjustments of the morning bolus dose, the maintenance 
dose and extra bolus doses should be carried out over a few weeks. 
 
 
  
 

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7. METHODS 
7.1 Study parameters/endpoints 
7.1.1 Main study parameter/endpoint 
Outcome parameters 
The primary health economic outcomes of the randomized trial are the costs per unit 
on the PDQ-39 and the costs per QALY for the cost-effectiveness and cost-utility 
analyses respectively. The EQ-5D will be applied as the utility measure. 
For a detailed motivation for outcome measures see appendix 13.3. 
7.1.2 Secondary study parameters/endpoints 
The main clinical outcome is quality of life (PDQ-39), Other secondary parameters 
are: 
PD motor symptoms (Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS), Clinical Dyskinesia Rating Scale (CDRS), 3-day motor 
symptom diary), non-motor symptoms such as autonomic functions and sleep (Non 
Motor Symptom Checklist, Rotterdam Symptom Checklist), neuropsychological and 
psychiatric assessment, possible cognitive decline on PD_CRS, Hoehn & Yahr 
stage, functional health status (ALDS), PD-medication, patient and physician 
preferences, Satisfaction with Life Scale, treatment satisfaction, adverse effects and 
complications, treatment failure, stopping treatment, starting with the alternative than 
initially started treatment, caregiver burden, (informal) care use and medical and 
non-medical care costs evaluated with the Institute for Medical Technology 
Assessment Productivity Cost Questionnaire (iMCQ) and Institute for Medical 
Technology Assessment Productivity Cost Questionnaire (iPCQ). 
7.1.3 Other study parameters 
When possible, a few baseline values will be collected from all patients, if possible 
including those not willing to be included in the patient preference trial study 
(anonymously), such as age, sex, medication, age of onset of PD, duration of PD, 
comorbidities, preference for treatment and possible reasons not to participate in the 
study. 
 
 
7.2 Randomisation, blinding and treatment allocation 
The randomization procedure will be website-based, using random blocks and stratified 
by:  

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level of experience of the including centre with DBS and CLI therapy (experienced DBS 
centres have treated at least 5 patients with DBS in the last two years and an experienced 
CLI centre has treated at least 5 patients with CLI each year in the last two years); 
 
7.3 Study procedures 
See also figure 1 and appendix 13.4 (assessment schedules). A patient can participate in 
the RCT after inclusion by the treating neurologist of a centre registered as a study site. 
Patients not willing to be randomized can participate in the patient prerefence trial in which 
only telephonic assessments will be executed either through 1. inclusion by the treating 
neurololgist in a centre registered as a study site; 2. providing contact information of the 
patient to the study team (approved by the patient) by a neurologist not registered as a 
study site whereafter the patient will be additionally informed by the team and informe 
consent will be signed; 3. direct registration by the patient with the INVEST study team, 
whereafter, if approved by the patient, the treating neurologist will be asked whether the 
patients fulfills the in- and exclusion criteria This procedure is described in 9.2, 
Recruitment and consent. 
 
 
 
RCT 
If the patient agrees to be randomized, a trial nurse will make an appointment for the first 
visit. There are eight specified assessment visits: at baseline and 1 week, 3 months, 6 
months, 9 months, 12 months, 24 months and 36 months after start of the study treatment 
(visits 1, 2, 3, 4, 5,6, 7 and 8). The last two assessments were added after the start of the 
trial. Additional follow-up might provide very relevant data on long term costs, side-effect 
and cross-over. Regarding visits 2, 3, 4, and 5, the visits for standard care in both CLI and 
DBS are extended with the questionnaires for the study or the patients will be interviewed. 
For the assessment schedule please see appendix 13.4, document F1 “Vragenlijsten” will 
give an outline of all used scales and questionnaires.  
 
At baseline (visit 1), age, sex, educational level, medication, age at onset of PD, duration 
of PD, Hoehn and Yahr stage, and comorbidities will be recorded. In addition, he or she 
will have an electrocardiogram (EKG), CT/MRI-scan of the head, and fasting blood 
analysis for sodium, potassium, creatinine, glucose, prothrombin time (PT), activated 
partial thromboplastin time (aPTT), leukocytes, erythrocytes, platelets. Vitamin B6, B12 
and folic acid will be analysed.  
Former participation in medical research and reason(s) to participate in this study will be 
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dyskinesias, and sleep states). The patients will have an assessment containing the MDS-
UPDRS and the AMC Linear Disability Score (ALDS) in standardized OFF and ON 
phases. The OFF phase is defined as the condition of the patient after withholding PD 
medication for 12 h and being awake for at least 1 h. The ON phase is the condition 1 h 
after a supra-threshold levodopa dose. The supra-threshold levodopa dose is based on 
the patient's usual first morning dose of PD drugs. To calculate the supra-threshold 
levodopa dose, different drugs will be pooled in Levodopa Equivalent Doses.  
The standardized OFF and ON phases examination will be videotaped. In the ON phase 
the patient will also undergo documentation of the Non Motor Symptom Checklist, 
Parkinson's Disease Impulsive-Compulsive Disorders Questionnaire, Hoehn and Yahr 
stage, ALDS, Rotterdam Symptom Checklist, Clinical Diskinesias Rating Scale (CDRS), 
patient-reported perceived quality of life (PDQ-39), EuroQol-5D (EQ-5D), iMTA Medical 
Consumption Questionnaire (iMCQ), iMTA Productivity Cost Questionnaire (iPCQ), use of 
(informal) care, apathy assessed by researcher and caregiver, caregiver burden and 
preference for treatment. The trial nurse will also administer the Mini-International 
Neuropsychiatric Interview (MINI) [20] and the Columbia Suicide Severity Rating Scale to 
screen psychiatric morbidity. The patients will undergo a neuropsychological examination 
including the Mattis Dementia Rating Scale and the Parkinson's Disease Cognitive Rating 
Scale (PD-CRS) and Patient-reported outcome tool for advanced Parkinson’s disease 
(PROAPD) and a standardized psychiatric assessment.  
 
After baseline screening, patients eligibility for both treatments will be discussed with the 
appropriate disciplines (neurology, neuropsychology, neurosurgery, and gastroenterology) 
in the treating centre, or the centre that will provide the treatment. If any possible contra-
indications for one of the treatments is found, the patient will be excluded from the study.  
Possible contra-indications are a non-dopamine responsive tremor as main complaint or if 
the effect of dopaminergic medication on motor symptoms is too small. Subsequently, the 
patient is randomized using a web-based application. Dependent on the result of 
randomization, the patient will be treated in the own hospital or he or she will be referred 
to one of the cooperating DBS centres. Within 3 months after the baseline assessment the 
study-treatment — DBS or CLI — will be started.  The treatment will be performed as 
described in section 5.1 
 
At visits 2, 3, 4, 5, 6, 7 and 8 patients will undergo documentation of PD-medication, 
adverse events (through a standardized questionnaire), treatment failure and cross-over. 
The iMCQ, iPCQ, use of (informal) care and caregiver burden are assessed at visit 3, 4, 5, 
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will keep a motor symptom diary (3 days; including ON/ OFF phases, dyskinesias, and 
sleep states) and the Non Motor Symptom Checklist, ALDS and patient satisfaction with 
the treatment. At visit 6 we will record the MDS-UPDRS, the CDRS and blood analysis as 
described above will be repeated. Also, patients will undergo a short neuropsychological 
examination and standardized psychiatric assessment at visit 6 and 8. The first year of 
follow-up, a margin of one month is deemed acceptable in planning a visit, for the second 
and third year of follow-up, the visits will be completed within two months of the defined 
follow-up date. 
 
 
Patient preference trial 
Patients that are not willing to participate in the RCT, but do take part in the ancillary 
patient preference observational study, will have a baseline visit with a limited set of 
evaluations. At the baseline visit, age, sex, medication, age at onset of PD, duration of 
PD, Hoehn and Yahr stage, and comorbidities will be recorded. The patients will have an 
assessment of the patient-reported perceived quality of life (PDQ-39) and will fill in a 
questionnaire on preference for treatment and expectations (PROADP). Follow-up visits 
are planned at 9 months, 12 months, 24 months and 36 months after the study treatment. 
In these visits, the PDQ-39 and patient satisfaction with the treatment will be assessed 
(PROADP), complications and adverse events will be evaluated using a questionnaire and 
the medical charts will be reviewed for complications and adverse events. If necessary, 
based on complications and adverse events questionnaire, the medical information from 
other hospitals will be requested and reviewed. The first year of follow-up, a margin of one 
month is deemed acceptable in planning a visit, for the second and third year of follow-up, 
the visits will be completed within two months of the defined follow-up date. 
 
 
Furthermore, during the study current preferences regarding treatment of advanced PD 
amongst treating physicians will be evaluated. 
 
7.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
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7.5 Follow-up of subjects withdrawn from treatment 
The analysis of the study will be based on the intention-to-treat principle. In case a patient 
stops the study-treatment (CLI or DBS), the authors will strive to continue the follow-up 
assessments. In other words, a patient that stops the study-treatment is not considered to 
be a dropout. We will record the number of patients that stop the assigned study-
treatment, the number of patients that crossover to the “other” study-treatment, and the 
number of patients that eventually need the “other” treatment in addition to the initially 
assigned study-treatment. Hence, these protocol violations are considered to be important 
secondary outcomes parameters of the study. 
 
7.6 Premature termination of the study 
There are no predefined reasons for termination of any of the study parts (randomized 
trial or patient preference observational study), as both DBS and CLI is regular care. 
 
 

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8. SAFETY REPORTING 
8.1 Temporary half for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed. 
 
8.2 AEs, SAEs and SUSARs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the experimental intervention or 
the investigational product. All adverse events reported spontaneously by the subject 
or observed by the investigator or his staff will be recorded in patients participating in 
the randomised controlled trial, from the moment patients undergo visit 1: screening 
until end of study. Since the patient preference study is observational, adverse events 
and SAEs will be reported using line listing.  
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any 
dose:  
1. results in death; 
2. is life threatening (at the time of the event); 
3. requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
4. results in persistent or significant disability or incapacity; 
5. is a congenital anomaly or birth defect; 
6. Any other important medical event that may not result in death, be life 
threatening, or require hospitalization, may be considered a serious adverse 
experience when, based upon appropriate medical judgement, the event may 
jeopardize the subject or may require an intervention to prevent one of the 
outcomes listed above. 
 

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If a SAE occurred in a patient randomised to one of the therapies, the principal 
investigator in the centre where the SAE occurred will notify the principal investigator 
in the coordinating centre by email or telephone within 24 hours. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 15 days after the sponsor has 
first knowledge of the serious adverse events. 
 
SAEs that result in death or are life threatening should be reported expedited. The 
expedited reporting will occur not later than 7 days after the responsible investigator 
has first knowledge of the adverse event. This is for a preliminary report with another 
8 days for completion of the report.  
 
Both procedures require a form of surgery and sedation. The procedures are 
performed in mainly elderly patients with a neurodegenerative disease. In these 
circumstances transient adverse effects like delirium or infections commonly cause 
prolonged hospitalization. Therefore, the categories concerning (prolongation of) 
hospitalization and “any other important medical event” will be reported to the 
accredited METC that approved the protocol in a twice-yearly line listing until the 
follow-up of the last patient is completed (categories 3 and 5). 
 
Furthermore, the following situations do not need to be reported as SAEs: 
• 
Any admission unrelated to an AE, e.g. cosmetic surgery, social and/or 
convenience admissions to a hospital; 
• 
Elective hospitalisation (planned before the subject consented for study 
participation) for pre-existing conditions that have not been exacerbated by study 
treatment as judged by the clinical investigator and where admission did not take 
longer than anticipated. 
• 
Admission for diagnosis or therapy of a condition that existed before receipt of 
study agent(s) and has not increased in severity or frequency as judged by the 
clinical investigator.  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present at the start of the study that do not worsen. 
• 
Protocol-specified admission, e.g., for a procedure required by the study protocol; 
 

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8.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 8.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in Summary of Product Characteristics (SPC) for an authorised 
medicinal product. 
 
If a SUSAR occurred, the principal investigator in the centre where the SUSAR 
occurred will notify the principal investigator in the coordinating centre by email or 
telephone within 24 hours. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
− SUSARs that have arisen in the clinical trial that was assessed by the METC; 
− SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal ToetsingOnline is 
sufficient as notification to the competent authority. 
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 

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8.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
− a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
− a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol.  
 
8.5 Pregnancy   
To ensure patient safety, each pregnancy must be reported to the Coordinating PI within 
24 hours of learning of its occurrence. As pregnancy is an exclusion criterion, the 
participant should be withdrawn from the trial. The pregnancy should be followed up for an 
appropriate period to determine outcome, including spontaneous or voluntary termination, 
details of the birth and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or new-born complications. Pregnancy should be recorded 
on a Clinical Trial Pregnancy Form. Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to investigational 
medicinal product of any pregnancy outcome. Any SAE experienced during pregnancy 
must be reported compliant with reporting procedures for a SAE.   
 
8.6 Data Safety Monitoring Board (DSMB) / Safety Committee] 
Since this open label trial consists of two routine treatments applied in regular daily 
practice, and participation in this study does not contain additional risks for patients (see 
chapter 12 for risk analysis) we consider this RCT, including the patient preference trial,  
as a negligible risk study. Therefore, no DSMB will be established.

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STATISTICAL ANALYSIS 
8.7 Primary study parameter(s) 
Statistical analyses will be based on the intention-to-treat principle. Baseline assessments 
and outcome parameters will be summarized using simple descriptive statistics. The main 
health economic analyses are a cost-effectiveness analysis based on costs and quality of 
life measured with the PDQ-39 and a cost-utility analysis, using the EQ-5D utility 
measure. (see also appendix 13.5 “Cost effectiveness analysis” and 13.6 “Patient 
Outcome Analysis”).  
 
8.8 Secondary study parameter(s)  
RCT 
The main clinical analysis of the study consists of a comparison between the trial 
treatment groups (DBS versus CLI) of the primary clinical outcome (PDQ-39) 12 months 
after the start of the study treatment. First, the follow-up difference between PDQ-39 
scores will be analysed using a two-group t-test. Second, the PDQ-39 follow-up scores 
will be further investigated using multiple linear regression taking into account patients' 
PDQ-39 baseline values, the stratifying variables (experience of the including centre with 
DBS and CLI; response to Levodopa) and (if necessary) for clinically relevant baseline 
imbalances. Additionally, the repeated data structure will be investigated with a linear 
mixed model. The same analyses will be performed for the 24 and 36 month outcomes.   
With regard to the comparisons of the other secondary outcomes PD motor symptoms 
(MDS-UPDRS, CDRS, 3-day motor symptom diary), non-motor symptoms such as 
autonomic functions and sleep (Non Motor Symptom Checklist, Rotterdam Symptom 
Checklist), PD-medication, neuropsychological and psychiatric assessment, disability, 
functional health status (ALDS), patient and physician preferences, patient satisfaction, 
adverse effects and complications, treatment failure, stopping treatment, starting with the 
alternative than initially started treatment, caregiver burden and medical and non-medical 
care costs (iMCQ, iPCQ) we will use the appropriate parametric and non-parametric 
statistics. In all analyses, statistical uncertainties will be expressed in 95% confidence 
intervals. 
 
Patient preference trial  
As mentioned before a patient preference observational study will be conducted to asses 
external validity of the randomized controlled trial results. The primary clinical outcome of 
the non-randomized group and randomized group will be compared using the two-group 
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two-group t-test and Chi-square test, when appropriate. Finally, the impact of the 
treatment on the PDQ-39 follow-up scores of the randomized and non-randomized group 
will be analysed using multiple linear regression, adjusting for relevant imbalanced 
baseline variables and randomized status (agreeing to randomization or not). 
 
8.9 Interim analysis (if applicable) 
. No interim analysis is planned. If patient recruitment shows to be falling behind, an 
interim analysis may become necessary, to evaluate if preliminary completion of the study 
is deemed feasible.   
 

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9. ETHICAL CONSIDERATIONS 
9.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version of 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO) and other guidelines, regulations and Acts. Study monitoring will be 
performed in accordance with the ICH GCP guidelines.  
 
9.2 Recruitment and consent 
Patients will be approached to participate in this study by their treating neurologist. The 
neurologist will check the inclusion and exclusion criteria in possible eligible patients. If 
the patient is eligible according to the criteria, the neurologist will inform the patient about 
the two treatment options and introduce the study. The patient will be asked permission to 
be contacted by members of the INVEST research team. Written information about the 
study will be provided to the patient, containing information on the 36 month follow-up 
period. (see E1-2, patient information). Patients will be given as much time needed to 
decide if they want to participate. Then, the neurologist or a member of the research team 
will ask the patient to participate in the randomized trial. The following 3 scenarios may 
then take place: 
• The patient wants to participate and agrees to be randomized. The patient signs the 
informed consent form in presence of a member of the research team and subsequently 
study Visit 1 is planned  
• The patient declines randomization, but agrees to participate in the patient preference 
observational arm of the study. The participant will receive the informed consent form with 
the first CRF by mail if not already signed during an outpatient visit. A member of the 
research team will call the participant to aid with the CRF, and asks the participant to send 
the signed consent form along with the first CRF.  
•The patient declines randomization. The neurologist records the patient characteristics. 
 
Furthermore, neurologists working in other hospitals in the Netherlands, that are not 
currently active INVEST study sites, may refer patients for the observational study. A 
member of the INVEST research team will contact the patient and supply patient 
information. The written consent will be acquired as described above at the second bullet 
point. Patients are allowed to contact the research team independently. With their 
permission, the research team will verify with their treating neurologist if the individual 
patient is eligible for the observational study. Subsequently, written consent will be 
acquired as described above.  

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9.2.1 Recruitment and consent for additional 24 and 36 month follow-up for 
participants already enrolled 
During the consent procedure for the 12 month follow-up, participants did or did not give 
permission to be contacted for further research. They have been informed about a 
pending additional follow-up period in the “Informatiebrief verlenging onderzoek” they 
received.  
The participants of the RCT, and the observational study who agreed to be contacted, will 
be asked by phone or mail to participate in the 24 and 36 month follow-up study. If 
interested, the patient is offered an optional informational meeting either in the hospital the 
patient was included in or at the home of the patient. If the patient want to participate in 
the extended follow-up, informed consent can be signed during this visit. If a patient wants 
to participate, but considers an informational meeting unnecessary, he or she will receive 
a separate 24 and 36 month follow-up informed consent form by mail. A member of the 
research team will call the participant to aid with said CRF, and asks the participant to 
send the signed consent form along with the first CRF.   
 
 
9.3 Benefits and risks assessment, group relatedness 
If patient agree to participate in the randomized controlled trial, patients will undergo 
regular treatment without additional risks. There is a small added burden of more and 
more detailed assessment procedures. We estimate these extra procedures — consisting 
of explanation of the research, questionnaires and motor symptom assessments — take 
approximately 15 hours for the 3 year follow-up, including time to travel to the hospital. 
This is a negligible risk according to the NFU (Nederlandse Federatie van Universitaire 
Medische Centra) criteria for human research. If patients do not agree to be randomized, 
but participate in the patient preference arms of the study, they will undergo regular 
treatment of their choice without any additional risks. The study related assessments take 
approximately 5 hours for patients participating in the patient preference observational 
study. 
 
9.4 Compensation for injury 
Since participation in this study does not entail additional risks because two regular 
treatments are compared, the METC has granted exemption to the obligation to take out 
liability insurance for the study subjects in accordance with article 7, subsection 9 of the 
WMO. 
 

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9.5 Incentives (if applicable) 
Patients will not receive incentives or privileges to participate in this study. Most DBS-
centres have a waiting list for treatment with DBS whereas treatment with CLI can be 
initiated at a relatively short notice (within 3 months). For optimal comparison of the 
therapies, in patients who participate in the study, start of treatment will be within three 
months of the baseline screening. This may be a motivation for patients to participate in 
the study. We do not expect that the waiting list for treatment with DBS will grow for 
patients not taking part in the study, as a proportion of patients that would otherwise be 
treated with DBS, will now be randomized for treatment with CLI.  

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
10.1 Handling and storage of data and documents 
The investigator will set up a Trial Master File at the beginning of the study. The list of 
essential documents will be in accordance with the GCP-guidelines. The essential 
documents that make up the file will be stored in a secure but accessible manner. All 
essential documents will be legible and accurate. The participating centres will keep 
copies of relevant documents, including essential centre-specific documents in their 
Investigator Files. 
 
After inclusion, the patient will be web-based randomized (TENALEA Clinical Trial Data 
Management System). This application will be made available by the Clinical Research 
Unit (CRU) of the AMC. 
 
For each randomized patient a digital Case Record Form (CRF) will be completed. The 
CRF consists of a sequential set of instructions with provision for data recording. All 
randomized patients are identified by a Patient Identification Number (PIN) in combination 
with a centre number. Trial personnel will not pass names outside the local hospital. The 
local investigator will ensure that patients' anonymity is maintained. On screening forms, 
digital or paper CRF’s or other documents submitted to the coordinating centre, patients 
will only be identified by a PIN in combination with a centre number. The subject 
identification code list will be safeguarded by the investigator. Data will be stored for 15 
years. Collected anonymised data may be used for future studies. 
 
10.2 Monitoring  
Academic Medical Center’s Clinical Research Unit (CRU) will provide independent 
monitoring according to the crafted monitorplan. After an initiation visit, monitoring will 
take place after 10 randomized patients at the principal site, and after 3 randomized 
patients at other sites. For more details, please consult the INVEST monitor plan. 
 
10.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 

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A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
10.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
10.5 End of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
10.6 Public disclosure and publication policy 
 The study is registered at the EudraCT trial register under number 2014-004501-32. The 
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11. STRUCTURED RISK ANALYSIS  
11.1 Potential issues of concern 
Not applicable, both treatment options are standard care. For further explanation see 
12.2. 
 
11.2 Synthesis 
The proposed research project involves treatment options that are standard care in daily 
practice in advanced PD. The therapies will not be combined with other investigational 
products. Both therapies have a small risk of severe complications and a larger risk of 
modest side-effects. There is a small-added burden of a more detailed assessment 
procedure. We estimate these extra assessments  —consisting of health(-economic) 
questionnaires and motor symptom assessments — to take approximately 10 hours, 
including time to travel to the hospital. Besides this small burden,  the study has no 
additional risk. Participation in the INVEST study constitutes a negligible risk according to 
the NFU-criteria for human research. 

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12. APPENDICES 
12.1 Contributing centres 
 
Centre 
Investigator on site 
Academisch Medisch Centrum 
Dr. J.M. Dijk 
Vrije Universiteit Medisch Centrum 
Dr. E.M.J. Foncke 
Spaarne Gasthuis Haarlem 
Dr. A.G. Munts 
Spaarne Gasthuis Hoofddorp 
Dr. M. Eurelings 
Canisius Wilhelmina Ziekenhuis 
Dr. C.C.P. Verstappen 
Onze Lieve Vrouwe Gasthuis 
Dr. A.M.M. Vlaar 
Flevoziekenhuis 
J.P. Blankevoort 
Maastricht UMC+ 
Dr. M.L. Kuijf 
Radboud Medisch Centrum 
Dr. R.A.J. Esselink 
Zuwe Hofpoort Ziekenhuis 
H. Hesselmans 
Zuyderland Medisch Centrum locatie Sittard 
Dr. P.H.M.F. van Domburg 
Zuyderland Medisch Centrum locatie Heerlen Dr. G. Tissingh 
Bronovo Ziekenhuis 
N. Weerkamp 
Hagaziekenhuis 
Dr. F. Contarino 
 

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12.2 Summary of Product Characteristics (SPC) of Duodopa 
The Duodopa SPC is attached to this application in Adobe .pdf format and is also 
available online on the site of the College ter Beoordeling van Geneesmiddelen 
(Medicines Evaluation Board) through the following link: http://www.cbg-meb.nl/, or via 
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12.3 Motivation for outcome measures  
To date, in most studies evaluating invasive treatments in advanced PD, the outcome is 
based on the recording of PD symptoms with the MDS-UPDRS, the time being in ON-
phase, the level of physical disability or perceived quality of life as measured with the 
PDQ-39. The mechanisms of action and procedures of both therapies are very different. 
For example, DBS treatment includes neurosurgery, implantation of stimulation 
equipment, and tuning of DBS-parameters in combination with gradual adjustments of the 
medication-schedule. In DBS, OFF-phase symptoms improve; and patients may 
experience this as more ON-phase time. DBS may influence behaviour and mood. In case 
of CLI, patients have a percutaneous endoscopic gastrostomy (PEG). During chronic CLI 
treatment, the pump has to be started every morning, it has to be removed every night, 
the PEG-stoma needs continuous care, and there is no change regarding OFF-phase 
symptoms, but OFF-phase time decreases and ON-phase time increases. The pump 
weights 0.5 kg. Considering all these aspects and patients’ preferences, using OFF-phase 
parkinsonism, time being in ON-phase, or physical disability as a primary outcome would 
be inadequate. Therefore we have chosen to use patient-reported perceived quality of life 
-- measured with the PDQ-39 -- as a primary clinical outcome and as the effect measure 
to be linked with costs in the cost-effectiveness analysis. In addition, the cost per QALY 
was chosen as the outcome measure of the cost-utility analysis to allow for comparisons 
of results from economic evaluations of different interventions within and across different 
disease populations and different health sectors. The EQ-5D will be applied as the utility 
measure. 
 
 
 
 

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12.4 Assessment schedules 
 
Visit 1 
Baseline 
Visit 
2 
1wk 
Visit 
3 
3mo 
Visit 
4 
6mo 
Visit 
5 
9mo 
Visit 
6 
12mo 
Visit 
7 
24mo 
Visit 
8 
36mo 
Baseline characteristics 
X 
 
 
EKG, CT/MRI brain 
X 
 
 
blood analysis 
X 
 
 
 
 
X 
 
 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
MDS-UPDRS motor score 
X 
X 
 
 
Clinical Dyskinesia Rating Scale (CDRS) 
X 
X 
 
 
Motor symptom diary (3 days) 
X 
X 
X 
X 
Non-motor symptom checklist 
X 
 
 
 
 
X 
X 
X 
Impulsive compulsive (QUIP) 
X 
 
 
 
 
X 
 
 
Apathy scale Starkstein (AS) 
X 
 
 
 
 
X 
 
 
Neuropsychological examination (incl. Mattis 
Dementia rating scale) 
X 
 
 
 
 
X 
 
X 
Mini-International Neuropsychiatric Interview 
X 
 
 
 
 
X 
 
 
Psychiatric assessment  
X 
 
 
 
 
X 
 
 
Hoehn and Yahr stage 
X 
 
 
 
 
X 
X 
X 
AMC disability scale (ALDS) 
X 
 
 
 
 
X 
X 
X 
PDQ-39 
X 
 
 
 
X 
X 
X 
X 
EQ-5D 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment preference 
X 
 
 
 
 
 
 
 
Treatment satisfaction 
 
 
 
 
 
X 
X 
X 
Satisfaction with life scale 
X 
 
 
 
 
X 
X 
X 
Treatment failures 
 
X 
X 
X 
X 
X 
X 
X 
Side effects/adverse events/complications 
 
X 
X 
X 
X 
X 
X 
X 
Crossover to other treatment 
 
 
X 
X 
X 
X 
X 
X 
iMTA Medical Consumption Questionnaire 
(iMCQ) 
X 
 
X 
X 
X 
X 
X 
X 
iMTA Productivity Cost Questionnaire (iPCQ) 
X 
 
X 
X 
X 
X 
X 
X 
Use of (informal) care 
X 
 
X 
X 
X 
X 
X 
X 
Caregiver burden 
X 
 
X 
X 
X 
X 
X 
X 
 

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Table 2: assessment schedule patient preference trial   
 
Visit 1 
Baseline 
Visit 2 
9mo 
Visit 3 
12mo 
Visit 4 
24mo 
Visit 5 
36 mo 
Baseline characteristics 
X 
 
 
 
 
Medication 
X 
X 
X 
X 
X 
Hoehn and Yahr stage 
X 
 
 
 
 
PDQ-39 
X 
X 
X 
X 
Treatment preference 
X 
 
 
Treatment satisfaction 
X 
X 
X 
Side effects/adverse events/complications 
 
X 
X 
X 
X 
Treatment failures and cross-over 
X 
X 
X 
X 
 
 
 

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12.5 Cost Effectiveness analysis (CEA) 
The economic evaluation of CLI against DBS treatment will be performed based on 
intention-to-treat as a cost-effectiveness and cost-utility analysis from a societal 
perspective with the costs per unit on the PDQ-39 and the costs per quality adjusted 
life-year (QALY) as the primary outcomes respectively. The primary outcome of the cost-
effectiveness analysis is closely related to the primary clinical outcome, the PDQ-39. The 
cost-utility analysis is considered mandatory to enable health policy makers allocating 
scarce health care resources across disease populations, across interventions, and 
across health sectors, based on explicit efficiency criteria. It is expected that CLI 
generates higher costs than DBS during the year of follow-up and should therefore 
sufficiently pay off compared with DBS in terms of increased effectiveness in order to be 
affordable for patient populations that might benefit from both treatments. It is yet unclear 
whether CLI actually pays off sufficiently.  
 
Incremental cost-effectiveness and cost-utility analyses will be performed for a 
willingness-to-pay value of €120,000 (for rationale, see sample size calculation) based on 
the net health benefit transformations of the respective incremental cost-effectiveness 
ratios and assuming reasonably normally distributed cost data. The time horizon in the 
study equals 1 year. With this time frame no discount rate will be applied for effects and 
costs to account for time preference. However, given the 5-year life-cycle of the studied 
devices (neurostimulator, tube, and pump) and the marked contrast of costs in the first 
year of treatment compared to subsequent years within the life-cycle period, we will 
depreciate the initial add-on intervention costs (placement of neurostimulator for DBS and 
tube and pump placement for CLI) over five years.  
One-way and multi-way probabilistic sensitivity analyses will be performed for the length 
of the friction period (3-6 months), and choice of UK rather than Dutch tariffs of time 
trade-off ratings of health states. 
Additional analyses will be performed with the assessments 24 and 36 months after start 
of treatment, to assess the longer term costs and benefits of both treatments more 
precisely. 
 
Cost analysis 
From the societal perspective the economic evaluation will include the direct medical as 
well as the direct and indirect non-medical costs of care. Indirect medical costs are not 
included as both treatments do not affect survival. All costs made by providers (index 
intervention and subsequent inpatient and outpatient health care), employers (loss of 
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expenses due to health care related travel, household assistance, over-the-counter 
medication) and their primary caregivers (non-reimbursable expenditures) will be 
quantified. 
 
 
Unit costing will be in accordance with the most recent update of existing national 
guideline as much as possible.[21]. Costs will be price-indexed for the base year 2014. 
Yearly consumer price indices will be used to standardize unit costs estimated in different 
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12.6 Patient outcome analysis 
 
Parkinson’s disease may seriously affect a person’s quality of life due to the physical 
symptoms and the psychological impact of having to cope with a chronic progressive 
condition. Adverse events of treatment too may affect how patients perceive their quality 
of life. To assess the health burden in the study population, the disease specific PDQ-39 
will be used. In addition, the EQ-5D will be applied as the utility measure in the cost-utility 
analysis. The EQ-5D has been validated in PD patients, strongly correlates with clinical 
scales, and is more sensitive in this patient group than the well-known, also generic Short 
Form-36 (SF-36).[16] The EQ-5D scoring profile can be converted into a utility score 
based on general population based tariffs of time trade-off ratings of health states. 
Initially, available Dutch tariffs [22] will be applied, while widely used UK tariffs [23] will be 
applied in the sensitivity analysis (see 13.5). For measurement frequency, see the 
paragraph concerning outcome parameters. Whereas patient preferences for the target 
interventions DBS or CLI matter, they have been incorporated into our patient 
preference trial design. If the health care efficiency results from the RCT turn out as 
indecisive, outcome analyses in the preference group become of further interest. 
 
 

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13. REFERENCES 
1. de Rijk, M.C., et al., Prevalence of Parkinson's disease in the elderly: the Rotterdam 
Study. Neurology, 1995. 45(12): p. 2143-6. 
2. Post B, P.M., Ziekte van Parkinson: Omvang van het probleem. Volksgezondheid 
Toekomst Verkenning, Nationaal Kompas Volksgezondheid, 2013. 
3. Poewe, W. and P. Mahlknecht, The clinical progression of Parkinson's disease. 
Parkinsonism Relat Disord, 2009. 15 Suppl 4: p. S28-32. 
4. Bloem BR, V.L.T., Keus SHJ, De Beer H, Poot E, Buskens E, Aarden W, Munneke M, 
Multidisciplinaire richtlijn Ziekte van Parkinson.  
, 2010. 
5. Katzenschlager, R., et al., Apomorphine subcutaneous infusion in patients with 
Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, 
double-blind, randomised, placebo-controlled trial. Lancet Neurol, 2018. 17(9): p. 
749-759. 
6. Valldeoriola, F., et al., Cost analysis of the treatments for patients with advanced 
Parkinson's disease: SCOPE study. J Med Econ, 2013. 16(2): p. 191-201. 
7. Fox, S.H., et al., The Movement Disorder Society Evidence-Based Medicine Review 
Update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord, 
2011. 26 Suppl 3: p. S2-41. 
8. Deuschl, G., et al., A randomized trial of deep-brain stimulation for Parkinson's disease. N 
Engl J Med, 2006. 355(9): p. 896-908. 
9. 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. 
10. 
Follett, K.A., et al., Pallidal versus subthalamic deep-brain stimulation for Parkinson's 
disease. N Engl J Med, 2010. 362(22): p. 2077-91. 
11. 
Odekerken, V.J., et al., Subthalamic nucleus versus globus pallidus bilateral deep 
brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised 
controlled trial. Lancet Neurol, 2013. 12(1): p. 37-44. 
12. 
Schuepbach, W.M., et al., Neurostimulation for Parkinson's disease with early motor 
complications. N Engl J Med, 2013. 368(7): p. 610-22. 
13. 
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. Lancet Neurol, 2014. 13(2): p. 141-9. 
14. 
Merola, A., et al., Comparison of subthalamic nucleus deep brain stimulation and 
Duodopa in the treatment of advanced Parkinson's disease. Mov Disord, 2011. 26(4): 
p. 664-70. 
15. 
Report of the "Nederlandse Vereniging voor Functionele Neurochirurgie bij 
Bewegingsstoornissen". 2013. 
16. 
Schrag, A., et al., The EQ-5D--a generic quality of life measure-is a useful instrument 
to measure quality of life in patients with Parkinson's disease. J Neurol Neurosurg 
Psychiatry, 2000. 69(1): p. 67-73. 
17. 
Kurth, M.C., et al., Oral levodopa/carbidopa solution versus tablets in Parkinson's 
patients with severe fluctuations: a pilot study. Neurology, 1993. 43(5): p. 1036-9. 
18. 
Nyholm, D., Duodopa(R) treatment for advanced Parkinson's disease: a review of 
efficacy and safety. Parkinsonism Relat Disord, 2012. 18(8): p. 916-29. 
19. 
Nyholm, D., et al., Duodenal levodopa infusion monotherapy vs oral polypharmacy in 
advanced Parkinson disease. Neurology, 2005. 64(2): p. 216-23. 
20. 
Sheehan, D.V., et al., The Mini-International Neuropsychiatric Interview (M.I.N.I.): the 
development and validation of a structured diagnostic psychiatric interview for DSM-
IV and ICD-10. J Clin Psychiatry, 1998. 59 Suppl 20: p. 22-33;quiz 34-57. 
21. 
Hakkaart- van Roijen, L., S.S. Tan, and C.A.M. Bouwmans, Handleiding voor 
Kostenonderzoek. in opdracht van het College voor Zorgverzekeringen, 2010. 
22. 
Lamers, L.M., et al., [Measuring the quality of life in economic evaluations: the Dutch 
EQ-5D tariff]. Ned Tijdschr Geneeskd, 2005. 149(28): p. 1574-8. 
23. 
Dolan, P., Modeling valuations for EuroQol health states. Med Care, 1997. 35(11): p. 
1095-108.