Cost-Effectiveness of Specialized Nursing Interventions for Patients With Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Radboud University Medical Center

NL65468.091.18  
 
PDNS 
 
 
 
 
 
 
 
 
 
 
 
 
Cost-effectiveness of specialized nursing 
interventions for patients with Parkinson’s disease 
 PROTOCOL 
(Version 2, 26-06-2018) 
 
ABR dossier-number NL65468.091.18 
 
 

NL65468.091.18  
 
PDNS 
 
 
 
PROTOCOL TITLE “Cost-effectiveness of specialized nursing interventions for patients with 
Parkinson’s disease” 
 
Protocol ID 
NL65468.091.18 
Short title 
PDNS 
Version 
First version 
Date 
26-06-2018 
Coordinating investigator/project 
leader 
Dr. Nienke de Vries 
Department of Neurology (935) 
Radboud university medical center 
PO Box 9101, 6500 HB Nijmegen 
Tel: 024-3614701 
Nienke.deVries-Farrouh@radboudumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
 
Prof. Dr. Bastiaan Bloem 
Department of Neurology (935) 
Radboud university medical center 
PO Box 9101, 6500 HB Nijmegen 
bas.bloem@radboudumc.nl 
Sponsor (in Dutch: verrichter/ 
opdrachtgever) 
Radboud university medical center 
Subsidising party 
ZonMw 
Laan van Nieuw Oost-Indië 334 
2593 CE Den Haag 
Postbus 93 245, 2509 AE Den Haag 
Tel: 070 349 51 11 
 
Zambon Company 
Via Lillo del Duca, 10 
Bresso 20091, Italy 
Tel: 003902665241 
Independent expert (s) 
Dr. Bart Post 
Department of Neurology (935) 
Radboud university medical center 

NL65468.091.18  
 
PDNS 
 
 
 
PO Box 9101, 6500 HB Nijmegen 
Tel: 024-3693653 
Bart.Post@radboudumc.nl 

NL65468.091.18  
 
PDNS 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of the department of Neurology 
 
 
Prof. Dr. Karin Klijn 
 
 
 
 
Coordinating investigator/project 
leader/principal investigator 
 
 
Dr. Nienke de Vries 
 
 
 
Prof. Dr. Bastiaan Bloem 
 
 
 
 
 
 
 

NL65468.091.18  
 
PDNS 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................14 
4.1 
Population (base) ...................................................................................................14 
4.2 
Inclusion criteria .....................................................................................................14 
4.3 
Exclusion criteria ....................................................................................................14 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................16 
5.1 
Investigational product/treatment ............................................................................16 
5.2 
Use of co-intervention (if applicable) ......................................................................16 
5.3 
Escape medication (if applicable) ...........................................................................17 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................18 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................18 
8. 
METHODS ....................................................................................................................19 
8.1 
Study parameters/endpoints ...................................................................................19 
8.1.1 
Main study parameter/endpoint .......................................................................19 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................19 
8.1.3 
Other study parameters (if applicable) .............................................................20 
8.2 
Randomisation, blinding and treatment allocation ..................................................20 
8.3 
Study procedures ...................................................................................................20 
8.4 
Withdrawal of individual subjects ............................................................................22 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................22 
8.5 
Replacement of individual subjects after withdrawal ...............................................23 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................23 
8.7 
Premature termination of the study .........................................................................23 
9. 
SAFETY REPORTING ..................................................................................................23 
9.2 
AEs, SAEs and SUSARs ........................................................................................24 
9.2.1 
Adverse events (AEs) ......................................................................................24 
9.2.2 
Serious adverse events (SAEs) .......................................................................24 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................25 
9.3 
Annual safety report ...............................................................................................25 
9.4 
Follow-up of adverse events ...................................................................................25 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................25 
10. 
STATISTICAL ANALYSIS ..........................................................................................26 
10.1 
Primary study parameter(s) ....................................................................................26 
10.2 
Secondary study parameter(s) ...............................................................................27 
10.3 
Other study parameters ..........................................................................................27 
10.4 
Interim analysis (if applicable) ................................................................................27 
11. 
ETHICAL CONSIDERATIONS ...................................................................................28 
11.1 
Regulation statement .............................................................................................28 

NL65468.091.18  
 
PDNS 
 
 
 
11.2 
Recruitment and consent........................................................................................28 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................28 
11.4 
Benefits and risks assessment, group relatedness .................................................29 
11.5 
Compensation for injury .........................................................................................29 
11.6 
Incentives (if applicable) .........................................................................................29 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................30 
12.1 
Handling and storage of data and documents ........................................................30 
12.2 
Monitoring and Quality Assurance ..........................................................................30 
12.3 
Amendments ..........................................................................................................31 
12.4 
Annual progress report ...........................................................................................31 
12.5 
End of study report .................................................................................................31 
12.6 
Public disclosure and publication policy ..................................................................31 
13. 
REFERENCES ..........................................................................................................32 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
7 of 33 
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) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
 
CRF(s) 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
Case Report Form(s) 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
 
PD 
PDNS 
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
Parkinson’s disease 
Parkinson’s Disease Nurse Specialist 
(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. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
8 of 33 
SUMMARY 
 
Rationale: The Dutch Multidisciplinary Guideline for Parkinson’s disease (PD) recommends 
that each PD patient should have access to Parkinson’s Disease Nurse Specialist (PDNS) 
care. Based on this recommendation, almost all Dutch hospitals now offer PDNS treatment. 
However, many hospitals lack the nursing capacity to offer care to all patients, creating 
unequal access to care and presumably avoidable disability and costs. This is at least partly 
due to lack of scientific evidence on the cost-effectiveness of PDNS care. We hypothesize 
that, by offering more patients access to PDNS care, quality of life will increase with equal 
healthcare costs. Increasing direct medical costs (for nurse staffing) will be offset by a 
reduced number of (telephone) consultations with the general practitioner and neurologist.  
Objective: We aim to study the cost-effectiveness of specialized nursing care provided by a 
PDNS as compared to no PDNS care for patients with PD in all disease stages.  
Study design: An 18-month single-blind randomised controlled trial (RCT).  
Study population: A total of 240 Dutch patients with PD (and their caregivers), male or 
female, age 18 years or older at the time of PD diagnosis, who are currently not treated by a 
PDNS and have not been treated by a PDNS over the past two years. Patients can be 
included regardless of disease duration or disease severity.  
Intervention (if applicable): Eight regional hospitals in the Netherlands will be included, 
where currently only a proportion of PD patients have access to PDNS care. Thirty patients 
in each hospital will randomly be allocated in a 1:1 ratio to either PDNS care according to the 
Dutch Guideline on PDNS care (2015), or no nursing intervention (usual care).  
Main study parameters/endpoints: We selected two co-primary outcome measures: quality 
of life measured by the PDQ-39 and motor symptoms measured by the MDS-UPDRS part III. 
The secondary outcome measures include, among others, non-motor symptoms, 
experienced quality of care, health-related quality of life, self-management, medication 
adherence, caregiver burden and healthcare utilization including costs.   
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The intervention evaluated in this study is non invasive and of very low 
risk, which therefore causes the risks associated with this study to be negligible. Also the 
burden associated with participation is limited. Patients will visit the PDNS based on their 
individual needs and preferences, which may vary from once a month to once every few 
months. These appointments may also be conducted by telephone. Patients will visit the 
researcher at baseline (t0), after 12 months (t1) and after 18 months (t2)), and each visit will 
take approximately one hour. Questionnaires will be filled out at home at t0, t1 and t2, taking 
one hour each time. Additionally, every three months patients will complete a short online 
questionnaire about healthcare costs, taking approximately 30 minutes to complete. 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
9 of 33 
1. INTRODUCTION AND RATIONALE 
 
Despite optimal medical management (medication or brain surgery), most patients with 
Parkinson’s disease (PD) experience progressive disability that increasingly influences their 
quality of life (1-5). Examples of motor symptoms that respond insufficiently to medical 
management include impairments in speech or balance. Additional disability arises from non-
motor symptoms (e.g. cognitive decline, depression), most of which are controlled poorly by 
medication (1,6). This creates tremendous challenges in advanced disease stages, and even 
early in the course of PD (7). 
 
There is increasing evidence that non-pharmacological management offers symptomatic 
relief of symptoms that are otherwise difficult to treat (8). Many healthcare disciplines can be 
involved in PD care. Physiotherapy has been studied most widely (8,9,10), but this cannot 
cover all PD-related problems. A more integral, multidisciplinary approach remains needed. 
 
The Parkinson’s Disease Nurse Specialist (PDNS) plays an essential role in the 
multidisciplinary team of people with PD. Here, we will study the cost-effectiveness of 
treatment by a PDNS, which was introduced to bridge the gap between medical 
management and the unique personal needs of patients (11). The recent Dutch guideline on 
PDNS care (2015) clearly describes the roles of a PDNS, including diagnostic strategies (e.g. 
detection of urinary retention or orthostatic hypotension) and therapeutic interventions (e.g. 
optimizing medication compliance, or strategies to alleviate orthostatic intervention) (12). 
Also, the PDNS assists patients and caregivers in their need of support, information, access 
to services and coordination of care (12). 
 
The Dutch Multidisciplinary Guideline for PD (13) recommends that each PD patient should 
have access to PDNS care. Based on this recommendation, almost all Dutch hospitals now 
offer PDNS treatment to their patients. However, many hospitals lack the nursing capacity 
that is needed to offer PDNS care to all patients, creating an undesirable inequality in access 
to care. Crucially, this situation offers a unique opportunity to now, for the first time, study the 
cost-effectiveness of PDNS intervention. Indeed, current evidence indicates that PDNS care 
may improve patient wellbeing, physical functioning and general health status, and reduce 
anxiety and depression (14,15,16). Also, scenario analyses (performed to estimate the 
potential cost-effectiveness of PDNS intervention) showed that PDNS treatment can be cost-
effective, provided the patients’ quality of life improves (14). However, there is little evidence 
to show that quality of life actually improves after PDNS intervention. 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
10 of 33 
 
Because of guideline recommendations (12,13) the PDNS has been implemented widely as 
an intervention in the Netherlands. However, in current practice there is great heterogeneity 
in delivery of PDNS care. Specifically, driven by lack of sufficient PDNS staff in most 
community hospitals, only a proportion of patients (mostly those with advanced disease) 
presently have access to a PDNS. This is at least partly due to the lack of scientific evidence 
on the cost-effectiveness of PDNS care. Yet, expert opinion dictates that all PD patients can 
benefit from PDNS interventions, including those with early-stage disease where e.g. delivery 
of information, advice about exercise, education about medication compliance, and support 
in self-management are critical. Consequently, care delivery remains suboptimal, fragmented 
and ineffective for many patients, presumably leading to unnecessary disability and 
avoidable costs. The Dutch multidisciplinary guideline therefore calls for an increase in 
PDNS capacity across the Netherlands, even though the cost-effectiveness of such a 
widespread implementation of PDNS care is unknown. 
 
This single-blind randomized controlled trial will provide information about the cost-
effectiveness of PDNS care. Furthermore, this study will permit more insight into the cost-
effectiveness of PDNS care in different subgroups of PD patients, based on disease 
duration. If the objectives are successfully reached, the chances of further implementation of 
PDNS care increases substantially, creating equal access to PDNS care for all PD patients.  
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
11 of 33 
2. OBJECTIVES 
 
Primary Objective: To study the cost-effectiveness of specialized nursing care provided by 
a Parkinson Disease Nurse Specialist (PDNS) as compared to no PDNS care for patients 
with PD in all disease stages. 
 
Secondary Objective(s): To perform a subgroup analysis based on disease duration, in 
order to gain more insight into the exact interventions used per disease stage and the effects 
of PDNS care in these different groups of patients: 
- Disease duration of <5 years (early, relatively uncomplicated phase) 
- Disease duration of 5-10 years (phase of response fluctuations) 
- Disease duration of >10 years (complicated phase) 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
12 of 33 
3. STUDY DESIGN 
 
This study is an 18-month Randomized Controlled Trial (RCT), which will be performed in 
eight community hospitals in the Netherlands. We consider this a monocenter study, 
because all research activities are carried out by a researcher from the Radboudumc. The 
neurologists in the community hospitals only deliver patients for inclusion and are not 
included in the research team. A total of 240 patients will be included, which implies 30 
patients in each hospital. We have selected hospitals where, due to lack of sufficient PDNS 
staff, only a proportion of PD patients currently has access to PDNS care. This gives us a 
unique opportunity to identify patients who currently have no access to PDNS care, and to 
randomize them within hospitals, and at the patient level, between PDNS care versus no 
nursing care.  
 
Eligible patients will be allocated randomly using a computerized sequence, in a 1:1 ratio, to 
either PDNS care or no nursing intervention (usual care). To ascertain an equal 
representation of representative patients, we will stratify for gender, age and disease 
duration (according to the pre-defined subgroups, i.e. <5 years, 5-10 years en >10 years). 
The PDNS intervention will be carried out according to the Dutch Guideline on PDNS care 
(2015) (12). A blinded researcher will perform an assessment of PD symptoms (Movement 
Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale), 
mobility (Timed up and Go Test) and bradykinesia (Pegboard Test) at three time points: prior 
to randomization (t0), after 12 months (t1) and after 18 months (t2). Caregivers will be asked 
whether they also agree to fill out questionnaires. Subsequently, patients and their caregivers 
will complete online questionnaires (Parkinson’s Disease Questionnaire, Hamilton Anxiety 
and Depression Scale, Scales for Outcomes in PD – Autonomic questionnaire, EuroQoL5D, 
Consumer Quality Index, Patient Activation Measure, Morisky Medication Adherence Scale, 
Zarit Caregiver Burden Index, CarerQol-7D, Utrechtse Proactieve Coping Competentielijst) at 
home at t0, t1 and t2. Finally, every three months patients and their caregivers will complete 
an online questionnaire about healthcare utilization and costs.   
 
The hospitals included in the trial are:  
- Maasziekenhuis Pantein in Boxmeer 
- Gelre Ziekenhuis in Zutphen 
- BovenIJ Ziekenhuis in Amsterdam 
- Careyn/St. Antonius Ziekenhuis in Utrecht 
- Waterlandziekenhuis in Purmerend 
- Rode Kruis Ziekenhuis in Beverwijk 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
13 of 33 
- TweeSteden/Elisabeth Ziekenhuis in Tilburg 
- Maxima Medisch Centrum in Eindhoven 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
14 of 33 
4. STUDY POPULATION 
4.1 Population (base)  
Dutch patients with Parkinson’s disease (n=240), male and female, age 18 years or older at 
the time of PD diagnosis. The subjects will be selected from the PD patient population of 
each of the included eight hospitals. The likelihood that each hospital can include 30 patients 
is high, because they have all checked the number of patients in their patient population that 
has not been treated by a PDNS over the past two years and indicated that the inclusion 
target is feasible.  
 
4.2 Inclusion criteria 
1. Patients with idiopathic Parkinson's disease: 
- that have sufficient knowledge of the Dutch language; 
- that were 18 years of older at the time of diagnosis;  
 - in all disease stages, regardless of disease severity or disease duration; 
 - who are currently not treated by a PDNS and who have not been treated by a PDNS in the 
past two years; 
- who have a score of ≥18 on the Mini-Mental State Examination (MMSE) and ≥12 on the 
Frontal Assessment Battery (FAB). 
 
4.3 Exclusion criteria 
1. Patients with a type of atypical parkinsonism caused by medication (e.g. neuroleptics), a 
metabolic disorder (e.g. Wilson’s disease), encephalitis or a neurodegenerative disorder (e.g. 
MSA, PSP). 
2. Patients with idiopathic PD that live in a nursing home or another type of residential care 
facility (because the PDNS is not operational there). 
3. Any other medical or psychiatric disorder that, in the opinion of the researcher, may 
compromise participation in the study.  
 
4.4 Sample size calculation 
 
We have selected two primary outcomes: PDQ-39 and MDS-UPDRS part III (motor score). 
The effect size for our sample size calculation is based on the PDQ-39 score, as observed in 
one of our previous studies in a similar population of PD patients, where we compared 
another type of healthcare intervention (multidisciplinary care) with usual care. We found a 
mean improvement in PDQ-39 score in the intervention group of -2.5 (SD: 5.8) points and a 
mean deterioration in PDQ-39 score in the control group of +1.4 (SD: 8.6). We calculated the 
sample size based on a mean difference between groups of 3.9, with a standard deviation 
of 8.6 (the highest SD reported) (17). Using a significance level of alpha=0.025 (instead of 
0.05 because of two primary endpoints) and a power of 80%, a sample of 93 patients in each 
group would be needed. Taking into account an attrition rate of 20% (which seems very 
reasonable based on our prior experience in large trials (9,10,17,18,19) where attrition rate 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
15 of 33 
was much lower than this), 117 patients are needed per group (a total of 234). We have 
rounded this up to 120 patients per group (a total of 240). This means that all eight 
participating hospitals need to include a total number of 30 patients. 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
16 of 33 
5. TREATMENT OF SUBJECTS 
 
 
 
5.1 Investigational product/treatment 
The PDNS intervention will be performed according to the Dutch Guideline on PDNS care 
published in 2015 (12). The intervention is not standardized, but tailored to the patients’ 
and caregivers’ needs. This includes the following aspects: 
1. Assessment of individual care needs of PD patients and their caregivers. The PDNS 
performs a specific nursing assessment related to the medical, physical, psychological 
and social domains. 
2. Development of a patient-centered treatment plan that supports patients and 
caregivers in self-management. The PDNS composes a multidisciplinary care plan, based 
on the results of the assessment, and as prioritized by the patient and caregiver (shared 
decision making). This treatment plan is developed according to the national self-
management framework (20). The PD nursing guideline includes a patient-centered 
treatment plan that describes all actions to be taken to realize patient-specific goals. 
 3. Specific nursing interventions. The nursing intervention varies across different disease 
stages and is always tailored to the specific problems and needs of individual patients 
and their caregivers. The PD nursing guideline describes specific interventions for the 
following problems: mental functions, fatigue, sleep, urogenital functions, sexuality, 
medication adherence, orthostatic hypotension, caregiver burden, coping, mobility, 
self-management, and dietary issues. Three general important PDNS interventions 
include: providing information and education, disease management (e.g. monitoring 
treatment effects, considering advanced treatment options such as Deep Brain 
Stimulation), and monitoring (e.g. screening on  non-motor symptoms, caregiver burden).  
4. Collaboration with other healthcare professionals. The PDNS stimulates and supports 
multidisciplinary collaboration between healthcare professionals based on the individual 
patient-centered plan. Furthermore, the PDNS plays a pivotal role in the timely referral to 
other healthcare workers. 
 
Patients have regular contact with their PDNS about the progress and realization of the 
personal goals, mostly by telephone, but also during face-to-face contacts and sometimes 
during additional home visits. The optimal frequency of contacts varies, depending on the 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
17 of 33 
disease stage and individual patient needs. 
 
Importantly, for the purpose of this study, we will implement an increase in nursing staff 
capacity of the existing nurses in the participating hospitals. This will allow us to study the 
real impact of adding PDNS care to current usual care. The participating PDNSs are all 
graduated nurses (education level according to the European Qualifications Framework 6 
or 7) with a certificate in Parkinson’s Nursing. Furthermore, they have achieved a 
standard of competences as described in the PD guideline. 
 
We will study the treatment given by these PDNS to patients with PD in all disease 
stages. Because of the large variation in problems encountered in different disease 
stages, the intervention will consist of a combination of actions tailored to each individual 
patient’s and caregiver’s needs. The usual care PDNS is trained to make such decisions 
about the optimal care for each patient based on an extensive assessment and 
continuous monitoring. 
 
We will compare PDNS care to continued PD care that is otherwise comparable, but 
without a nursing intervention. Specifically, PD patients in the control group (who will be 
matched for baseline characteristics to the intervention patients) will receive usual care 
without any form of nursing care, but with no restrictions to any other medical treatments. 
This can be achieved by randomizing comparable patients within hospitals, so that other 
important elements of care (including in particular the treating neurologist) remain 
comparable between the two intervention arms.  
 
5.2 Use of co-intervention (if applicable) 
NOT APPLICABLE 
 
5.3 Escape medication (if applicable) 
 
NOT APPLICABLE 
 
 
 
 
 
 
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
18 of 33 
6. INVESTIGATIONAL PRODUCT  
NOT APPLICABLE 
 
 
 
7. NON-INVESTIGATIONAL PRODUCT 
NOT APPLICABLE 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
19 of 33 
8.  METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The co-primary outcome measures of the study are: 
 
Outcome measure 
Scale/questionnaire 
Quality of life 
Parkinson’s Disease Questionnaire (PDQ-39) 
Motor symptoms 
Movement Disorders Society-sponsored revision of the 
Unified Parkinson’s Disease Rating Scale part III (MDS-
UPDRS part III) 
 
8.1.2 Secondary study parameters/endpoints (if applicable) 
The secondary outcome measures of the study are: 
 
Patient-related outcome measures 
 
Outcome measure 
Scale/questionnaire 
Longitudinal PD symptoms 
Movement Disorders Society-sponsored 
revision of the Unified Parkinson’s 
Disease Rating Scale Part I, II, IV 
Mobility 
Timed Up and Go Test (TUG) 
Bradykinesia 
Pegboard Test 
Non-motor symptoms (anxiety and 
depression) 
Hamilton Anxiety and Depression Scale 
(HADS) 
Non-motor symptoms (e.g. sleep, 
cognition, urinary tract problems and 
constipation) 
Scales for Outcomes in Parkinson’s 
Disease – Autonomic questionnaire 
(SCOPA-AUT) 
Health-related quality of life 
EuroQoL5D (EQ5D) 
Experienced quality of care 
Consumer Quality Index (CQI) 
Self-management 
Patient Activation Measure (PAM) 
Medication adherence 
Morisky Medication Adherence Scale 
(MMAS) 
 
Caregiver-related outcome measures 
 
Outcome measure 
Scale/questionnaire 
Health-related quality of life 
EuroQoL5D (EQ5D) 
Caregiver burden 
Zarit Caregiver Burden Index (ZBI) 
Caregiver quality of life  
CarerQol-7D 
Skills of proactive coping 
Utrechtse Proactieve Coping 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
20 of 33 
Competentielijst (UPCC) 
 
Healthcare consumption and costs 
 
Outcome measure 
Scale/questionnaire 
Medical consumption of the patient 
Medical Consumption Questionnaire 
(MCQ) 
Productivity loss of working PD patients 
Productivity Cost Questionnaire (PCQ) 
Productivity loss of caregivers 
Cost questionnaire specifically aimed at 
caregivers 
 
8.1.3 Other study parameters (if applicable) 
Not applicable. 
 
8.2 Randomisation, blinding and treatment allocation 
Eligible patients will be randomized within hospitals, and at the patient level, between 
the PDNS care intervention group and the control group (no nursing intervention, 
usual care). Patients will be allocated randomly using a computerized sequence, in a 
1:1 ratio, and we will stratify for age, gender and disease duration. The randomization 
code will be prepared by an independent statistician and performed by Dr. Nienke de 
Vries-Farrouh, project leader, since the study is single-blind and the researcher 
performing the MDS-UPDRS, TUG, Pegboard Test and the data analysis will be 
blinded for group allocation. Patients will receive a unique personal identification code 
that refers back to the name of the study (e.g. PDNS01, PDNS02, etc): a consecutive 
number based on the order of enrolment. 
 
8.3 Study procedures 
Patients will be approached for participation using three scenarios. In the first scenario, 
the involved neurologists in each participating center will identify eligible patients from 
their electronic patient file and inform these patients in their clinic about the study. They 
will also specifically ask the patients whether they agree with providing the researcher with 
their personal telephone number. If these patients agree to be approached by a 
researcher, they will be provided with the patient information letter. A researcher from the 
Radboudumc will contact the patient by telephone after 7 days to answer questions and 
obtain consent for participation.  
In the second scenario, neurologists in each hospital will also identify eligible patients 
using their electronic patient file and subsequently approach them by directly sending out 
a letter (‘voorbrief’) including a short description of the study. This will also include a self-
addressed envelope, and if patients want to be approached, they can sign and send back 
a short form (saying “I want to receive further information about the study and the 
researcher is allowed to contact me by telephone”), using this self-addressed envelope. 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
21 of 33 
We will ask the patient to directly fill out their telephone number on the form, so that we do 
not have to obtain this number from the patient file. Also if patients do not want to be 
approached, they can sign and send back the short form (saying “I do not want to receive 
any further information about the study and I do not wish to be approached”), using this 
self-addressed envelope. If we do not receive any reply, the patient will not be contacted. 
If the patient is interested to participate, the researcher will send the patient information 
letter. After one week, the researcher will contact the patient again to answer questions 
and obtain consent for participation.  
In the third scenario, we will organise an ‘information meeting’ for patients in the 
participating center (where also the PDNS and neurologist may be present). Patients will 
be invited for this meeting by their treating neurologist. After the information meeting, 
patients can register with the research team by providing their telephone number. Patients 
will also be provided with the patient information letter. When patients require more time to 
consider participation, they will also receive with the patient information letter and a 
‘registration card’ which they can fill out at home and send back directly to the research 
team. On this registration card, permission will be asked for being contacted by the 
researcher” The researcher will contact each patient after seven days to answer questions 
and obtain consent for participation. In each center one of these scenarios will be chosen 
based on the preferences of the center. However, the first and second scenario are 
preferred and the third scenario (information meeting) will only be used when inclusion 
rates are insufficient.  
 
During the study period, patients will be in contact with their PDNS based on their 
individual needs and preferences. These appointments may also be conducted by 
telephone. The amount of contact may vary from once a month to once every few months. 
However, currently in the Netherlands on average patients are seen by their PDNS twice 
a year, with other two interim telephone consultations per year.  
 
At baseline (t0), each patient will visit his/her own hospital, where the Radboudumc 
researcher will obtain informed consent. Afterwards, the MDS-UPDRS, TUG and 
Pegboard Test will be performed. This appointment will take approximately 60 minutes. 
Furthermore, the patients will complete a set of questionnaires at home, online or on 
paper (PDQ-39, HADS, SCOPA-AUT, EQ5D, CQI, PAM, MMAS), which will also take 
approximately 60 minutes to complete. The caregiver will complete the EQ5D, ZBI, 
CarerQol-7D and UPCC, which takes approximately 30 minutes to complete.  
 
After 12 months (t1) and after 18 months (t2) the patient will visit the Radboudumc 
researcher again in his/her own hospital. Also then, the MDS-UPDRS, TUG and Pegboard 
Test will be performed. Furthermore, patients will complete the same set of questionnaires 
at home, online or on paper (PDQ-39, HADS, SCOPA-AUT, EQ5D, CQI, PAM, MMAS). 
The caregiver will complete the EQ5D, ZBI, CarerQol-7D and UPCC. 
 
Every three months, patients will complete a questionnaire regarding healthcare utilization 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
22 of 33 
and costs over the past three months, to be completed online or on paper (MCQ). This 
questionnaire takes approximately 30 minutes to complete. Patients that are still working 
will also complete the PCQ, which takes approximately 20 minutes to complete. 
Caregivers will complete a cost questionnaire specifically aimed at caregivers, taking 
approximately 20 minutes to complete.  
 
Data from all paper-based questionnaires (MDS-UPDRS, TUG, Pegboard Test) and 
online CRFs (the remaining questionnaires) will be entered manually into the data 
management system Castor. When patients are not able to fill out questionnaires online, 
they also have the opportunity to do this on paper. We will then send out the 
questionnaires and patients can send the completed questionnaires back by post. We will 
compile a Trial Master File (TMF) in the Radboudumc where all original collected data will 
be safely stored. The original signed informed consent forms and copies of the collected 
data will be stored in the participating center in an Investigator Site File.  
 
8.4 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 urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
Currently, PDNS care is not ‘usual care’. Therefore, there are no strict indications 
for PDNS care. However, when the treating physician considers the overall health 
of the patient in the control group compromised by not receiving care from a PDNS, 
these patients will withdraw from the study and receive this care. This will be 
reported to the researchers. However, this patient will still be evaluated at the pre-
defined measurement points, following the intention-to-treat principle.  
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
23 of 33 
8.5 Replacement of individual subjects after withdrawal 
Patients who withdraw will not be replaced. In the sample size calculation, we have 
taken into account an attrition rate of 20%. This gives our study enough power to 
complete, even if 24 patients in each group will be withdrawn.  
 
8.6 Follow-up of subjects withdrawn from treatment 
Following the intention to treat principle, we will see every included patient at the 
pre-defined follow-up appointments (baseline, after 12 months, and after 18 
months). Therefore, when patients are withdrawn from the control group because 
they need PDNS care, we will still perform the follow-up measurements.  
 
8.7 Premature termination of the study 
We cannot think of any direct reason why the study would be prematurely terminated, 
because the study intervention is of very low-risk. We cannot guarantee that we will 
achieve the aimed inclusion rate of 240 patients (however, we do think that this is very 
feasible (see paragraph 4.1)). Furthermore, the inclusion may be slower than initially 
expected. In these cases, the study may temporarily be delayed and adjustments will 
be made before continuation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
24 of 33 
 
 
 
 
 
 
9. SAFETY REPORTING 
9.1 Temporary halt 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.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 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 
by the PDNS. All adverse events reported spontaneously by the subject or observed 
by the investigator or his staff will be recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
25 of 33 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable. 
 
9.3 Annual safety report 
 
Not applicable. 
 
9.4 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. 
 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
Not applicable.  
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
26 of 33 
10. STATISTICAL ANALYSIS 
 
10.1 Primary study parameter(s) 
Statistical analyses will be performed based on the intention-to-treat principle. We will 
include study center as a random effect, and fixed effects for group, time, and the 
interaction between group and time. Each of the outcomes will be included as dependent 
variables. Baseline values, center, age at baseline, Hoehn & Yahr stage and disease 
duration will serve as covariates. Missing data will be imputed, patients with missing data 
will therefore be included in the analysis.  
 
The cost-effectiveness evaluation investigates, alongside the clinical trial, the value for 
money of full implementation of the PDNS into PD care from a societal and healthcare 
perspective. We will take all relevant costs into account. A health perspective will be 
presented as a scenario (and potential input for the Budget Impact Analysis). The CEA 
timeframe adheres to the clinical study protocol and evaluates cost-effectiveness up to 12 
months after randomization. Cost will be measured using a healthcare utilization 
questionnaire. We will use a PD-specific quality of life measure (PDQ-39) and a generic 
quality of life scale (EQ5D-5L) to evaluate effects. We hypothesize that both interventions 
(PDNS care versus no PDNS care) will yield equal costs, while PDNS care is more 
effective. If this hypothesis is confirmed, then the effect analysis is sufficient to show the 
efficiency of the PDNS. The design of the economic evaluation follows the principles of a 
cost-effectiveness analysis and adheres to the Dutch guideline for performing economic 
evaluations in health care (22). Costs will be analyzed using a mixed model approach or 
a generalized linear model approach with a gamma distribution using a log link to account 
for possible skewness of the cost data. QALYs with the EQ-5D 5L will be calculated using 
the trapezium rule. The potential difference in QALYs will be researched with a regression 
approach. 
 
The cost analysis exists of two main parts. First, on patient level, volumes of care will be 
measured prospectively over the time path of the study using patient level questionnaires 
and Case Report Forms (CRFs), complemented, if necessary, by data from the hospital 
administration system. The CRF will be developed in a way that it structures and uniforms 
healthcare consumption for this particular target population. 
 
Second, per item of healthcare consumption, standard cost-prices will be determined 
using the guideline for performing economic evaluations (22). If standardized prizes are 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
27 of 33 
not available full cost prices will be determined using activity based costing. Productivity 
losses for patients and caregivers will be assessed using the Productivity Cost 
Questionnaire or elements from it. The friction cost-method will be applied following the 
Dutch guidelines (22). 
 
10.2 Secondary study parameter(s)  
We will use a linear mixed model with repeated measurements to test for differences in 
quality of life (measured with the PDQ-39) between both groups. The same analysis will 
be used to measure differences between groups in the other secondary outcome 
measures (MDS-UPDRS part I, II, IV, TUG, Pegboard Test, HADS, SCOPA-AUT, EQ5D, 
CQI, PAM, MMAS, ZBI, CarerQoL-7D, UPCC, and healthcare costs).  
 
The PDQ-39 is the most comprehensive and widely used instrument to measure PD-
specific quality of life. It consists of 39 items and is organized in 8 domains (mobility, 
activities of daily living, emotional well-being, stigma, social support, cognition, 
communication and pain) and a summary index. 
 
To measure the quality of the health status of the patients, a validated so-called health 
related quality of life (HRQoL) instrument will be used, the EuroQol-5D (21). This HRQoL 
instrument will be completed by patients and is available in a validated Dutch translation 
(EQ-5D-5L) (ZIN, 2015). The EQ-5D is a generic HRQoL instrument comprising five 
domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
EQ-5D index is obtained by applying predetermined weights to the five domains. This 
index gives a societal-based global quantification of the patient’s health status on a scale 
ranging from 0 (death) to 1 (perfect health). Patients will also be asked to rate their overall 
HRQoL on a visual analogue scale (EQ- 5D VAS) consisting of a vertical line ranging from 
0 (worst imaginable health status) to 100 (best imaginable) (21). 
 
10.3 Other study parameters 
Not applicable.  
 
10.4 Interim analysis (if applicable) 
In view of the objective of this study, we will not perform an interim analysis.  
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
28 of 33 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted in accordance with the Good Clinical Practice (GCP) 
guidelines promulgated by the International Conference on Harmonization (ICH), the 
principles of the Declaration of Helsinki (version 7, 2013), and the Medical Research 
Involving Human Subjects Act (WMO).  
 
11.2 Recruitment and consent 
This study will be conducted in accordance with the provisions of 21 Code of Federal 
Regulations (CFR) Part 50. As described in paragraph 8.3, two scenarios will be used for 
recruitment, depending on the preferences of participating hospitals. If patients agree to 
be approached by a researcher using either of these two scenarios, a Radboudumc 
researcher will contact the patient by telephone after 7 days to answer questions and to 
discuss the consent. In accordance with relevant regulations, an informed consent 
agreement explaining the procedures and requirements of the study, how subjects’ 
confidentiality will be maintained, and any potential hazards/risks will be explained to 
each subject. Each subject will sign such an informed consent form in-person at the 
baseline visit, before baseline assessment takes place. The researcher will sign the 
informed consent form immediately after the subject has signed it. The subject is assured 
of the freedom to withdraw from participation in the study at any time. The original signed 
consent form is in the participating center and each subject will receive a copy of the 
signed consent form. 
 
The consent process for each subject who signs the informed consent form will be 
documented in the subject’s source (e.g., research file, research progress note) and 
includes the title of the study, that the consent was discussed with an opportunity for 
questions and answers, how the subject demonstrated comprehension, that the consent 
was signed prior to the first study procedure, and that the subject received a signed copy 
of the consent. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
29 of 33 
11.4 Benefits and risks assessment, group relatedness 
The intervention evaluated in this study is non invasive and of very low risk, which 
therefore causes the risks associated with this study to be negligible. The risk not 
associated with this intervention itself, but rather with the organization of PDNS care in the 
Netherlands, consists of the following: during the study, each hospital receives budget to 
increase their PDNS capacity to provide care to 15 patients in the intervention group. 
However, when the study is finished, there is a chance that PDNS care for these patients 
will be cancelled because the extra nursing capacity is no longer paid by the study. Each 
hospital will, in the end, make its own decisions regarding the continuation of care for the 
patients participating in the study. The 15 patients in the control group will not be allowed 
to receive PDNS care during the study period.  
 
PDNS care is currently only partially implemented in the Netherlands, and therefore not 
‘usual care’. The 240 patients included in this study do not receive PDNS care at the 
moment, mainly due to a lack of scientific evidence of its cost-effectiveness. With positive 
results, it is more likely that PDNS care will be further implemented for all PD patients. In 
addition, it is possible that, in the case of positive patient experiences, participating 
hospitals will increase their own budget for increasing PDNS capacity. Furthermore, 
besides PDNS care, there are no restrictions to other medical treatments for the patients 
in the control group, and they can visit all other available healthcare providers (e.g. 
physiotherapist, psychologists).  
 
11.5 Compensation for injury 
In accordance with article 7 of the WMO, we will submit a written request for exemption 
from the liability insurance. If this request is not accepted, we will submit an amendment 
and include information about the liability insurance below.  
 
11.6 Incentives (if applicable) 
We will offer compensation for travel expenses to all subjects for travelling to the hospital 
for the assessments on t0, t1 and t2.  
 
Each participating hospital will receive compensation for the increased PDNS capacity, 
which includes 65 Euros per hour (= 4 hours per week). In case of unforeseen extra 
healthcare costs, there is room to expand this compensation up to a certain extent.   
 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
30 of 33 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
1. Data from all paper-based CRFs (MDS-UPDRS, TUG, Pegboard Test) will be entered 
manually into a data management system (Castor). Online CRFs (the remaining 
questionnaires) will automatically be recorded in Castor. CRFs only contain a personal 
identification code. This means that patients are given a personal unique identification code 
(e.g. PDNS01, PDNS02, etc). The executive researchers (Dr. Nienke de Vries-Farrouh and 
Drs. Danique Radder) own the key and will be able to track back data to the individual 
patient. Additionally, only the assigned research team has exclusive authorization rights to 
access data. Personal data will be kept separately from the experimental data acquired.  
2. Clinical notes taken by the PDNS during the initial assessment and follow-up will be 
documented in a pre-defined paper-based study diary according to a structured format, using 
the unique personal identification code. PDNS are instructed to make notes according to this 
structured format, without mentioning personal information that traces back to an individual 
patient. We will collect this information because we want to obtain information on what exact 
interventions have been used by the PDNSs, to be used for a process analysis at the end of 
the study. The study diary will be handed over to the research team after the last patient has 
completed the 18-month follow-up.  
 
12.2 Monitoring and Quality Assurance  
Data-entry errors will be checked by re-entering a sample of 5% of all CRFs, in an 
emptied copy of the original data-entry format. An independent monitor from the Clinical 
Research Center Nijmegen (CRCN) will be appointed to check the following: 
1. 10% of informed consent forms (n=24) 
2. 5% on in- and exclusion, plus the first three participants (n=15) 
3. 5% source document verification (n=12) 
4. 5% on SAEs and SUSARs (n=12) 
 
In case of substantial errors, monitoring intensity will be increased. Monitoring starts after 
the baseline assessments of the first 5 patients have been entered and continues until 
the last CRFs have been entered in the database. 
 
In addition, the coordinating researcher will check the quality of data-entry and handling 
by the research team on a continuous basis.  
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
31 of 33 
12.3 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.  
 
12.4 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.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
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.  
 
12.6 Public disclosure and publication policy 
The sponsors ZonMw and Zambon will not in any way be involved in the manuscripts and 
abstracts that result from the study data. ZonMw and Zambon will be cited as a funding 
source.  
 
The study will be registered in the public trial registry ClinicalTrials.gov on short notice. 
 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
32 of 33 
13.  REFERENCES 
 
1. Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet 2009;373(9680):2055-2066. 
2. Sprenger F, Poewe W. Management of motor and non-motor symptoms in Parkinson's 
disease. CNS drugs 2013;27(4):259-272. 
3. Lyons KE, Pahwa R, Troster AJ, Koller WC. A comparison of Parkinson's disease 
symptoms and self reported functioning and well being. . Parkinsonism & related disorders 
1997;3:207-209. 
4. Moore O, Peretz C, Giladi N. Freezing of gait affects quality of life of peoples with 
Parkinson's disease beyond its relationships with mobility and gait. Movement disorders, 
2007;22(15):2192-2195. 
5. Bloem BR, van Vugt JP, Beckley DJ. Postural instability and falls in Parkinson's disease. 
Advances in neurology 2001;87:209-223. 
6. Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society Evidence-Based 
Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. 
Movement disorders : official journal of the Movement Disorder Society 2011;26 Suppl 
3:S42-80. 
7. Goetz CG, Pal G. Initial management of Parkinson's disease. BMJ (Clinical research ed) 
2014;349:g6258. 
8. Bloem BR, de Vries NM, Ebersbach G. Nonpharmacological treatments for patients with 
Parkinson's disease. Movement disorders: official journal of the Movement Disorder Society 
2015;30(11):1504-1520. 
9. van der Marck MA, Munneke M, Mulleners W, et al. Integrated multidisciplinary care in 
Parkinson's disease: a non-randomised, controlled trial (IMPACT). The Lancet Neurology 
2013;12(10):947-956. 
10. Munneke M, Nijkrake MJ, Keus SH, et al. Efficacy of community-based physiotherapy 
networks for patients with Parkinson's disease: a cluster-randomised trial. The Lancet 
Neurology 2010;9(1):46-54. 
11. MacMahon DG. Parkinson's disease nurse specialists: an important role in disease 
management. Neurology 1999;52(7 Suppl 3):S21-25. 
12. Lennaerts-Kats HH, et al. Richtlijn Verpleegkundige zorg bij de ziekte van Parkinson. 
Alphen aan den Rijn 2015. 
13. Bloem BR, et al. Multidisciplinaire richtlijn ‘Ziekte van Parkinson’. Alphen aan den 
Rijn2010. 
14. Jahanshahi M, Brown RG, Whitehouse C, Quinn N, Marsden CD. Contact with a nurse 
practitioner: a short-term evaluation study in Parkinson's disease and dystonia. Behavioural 
neurology 1994;7(3):189-196. 

NL65468.091.18  
 
PDNS 
Version 2, June 26th 2018 
 
33 of 33 
15. Jarman B, Hurwitz B, Cook A, Bajekal M, Lee A. Effects of community based nurses 
specialising in Parkinson's disease on health outcome and costs: randomised controlled trial. 
BMJ (Clinical research ed) 2002;324(7345):1072-1075. 
16. Reynolds H, Wilson-Barnett J, Richardson G. Evaluation of the role of the Parkinson's 
disease nurse specialist. International journal of nursing studies 2000;37(4):337-349. 
17. van der Marck MA, Bloem BR, Borm GF, Overeem S, Munneke M, Guttman M. 
Effectiveness of multidisciplinary care for Parkinson's disease: a randomized, controlled trial. 
Movement disorders; 2013;28(5):605-611. 
18. van Nimwegen M, Speelman AD, Overeem S, et al. Promotion of physical activity and 
fitness in sedentary patients with Parkinson's disease: randomised controlled trial. BMJ 
(Clinical research ed) 2013;346:f576. 
19. Sturkenboom IH, Graff MJ, Hendriks JC, et al. Efficacy of occupational therapy for 
patients with Parkinson's disease: a randomised controlled trial. The Lancet Neurology 
2014;13(6):557-566. 
20. CBO. Zorgmodule Zelfmanagement 1.0. Utrecht: CBO; 2014. 
21. M MV, K MV, S MAAE, de Wit GA, Prenger R, E AS. Dutch Tariff for the Five-Level 
Version of EQ-5D. Value in health: the journal of the International Society for 
Pharmacoeconomics and Outcomes Research 2016;19(4):343-352. 
22. Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidszorg. Online 
available: Zorginstituut Nederland; 2016.