Radder et al.

Trials (2020) 21:88

[Link]

STUDY PROTOCOL Open Access

The cost-effectiveness of specialized

nursing interventions for people with
Parkinson’s disease: the NICE-PD study
protocol for a randomized controlled
clinical trial
Danique L. M. Radder1* , Herma H. Lennaerts2, Hester Vermeulen3, Thies van Asseldonk4,
Cathérine C. S. Delnooz5, Rob H. Hagen6, Marten Munneke1, Bastiaan R. Bloem1 and Nienke M. de Vries1

Abstract
Background: Current guidelines recommend that every person with Parkinson’s disease (PD) should have access to
Parkinson’s disease nurse specialist (PDNS) care. However, there is little scientific evidence of the cost-effectiveness
of PDNS care. This hampers wider implementation, creates unequal access to care, and possibly leads to avoidable
disability and costs. Therefore, we aim to study the (cost-)effectiveness of specialized nursing care provided by a
PDNS compared with usual care (without PDNS) for people with PD in all disease stages. To gain more insight into
the deployed interventions and their effects, a preplanned subgroup analysis will be performed on the basis of
disease duration (diagnosis < 5, 5–10, or > 10 years ago).
Methods: We will perform an 18-month, single-blind, randomized controlled clinical trial in eight community
hospitals in the Netherlands. A total of 240 people with PD who have not been treated by a PDNS over the past 2
years will be included, independent of disease severity or duration. In each hospital, 30 patients will randomly be
allocated in a 1:1 ratio to receive either care by a PDNS (who works according to a recent guideline on PDNS care)
or usual care. We will use two co-primary outcomes: quality of life (measured with the Parkinson’s Disease
Questionnaire-39) and motor symptoms (measured with the Movement Disorders Society-sponsored revision of the
Unified Parkinson’s Disease Rating Scale part III). Secondary outcomes include nonmotor symptoms, health-related
quality of life, experienced quality of care, self-management, medication adherence, caregiver burden, and coping
skills. Data will be collected after 12 months and 18 months by a blinded researcher. A healthcare utilization and
productivity loss questionnaire will be completed every 3 months.
Discussion: The results of this trial will have an immediate impact on the current care of people with PD. We
hypothesize that by offering more patients access to PDNS care, quality of life will increase. We also expect
healthcare costs to remain equal because increases in direct medical costs (funding additional nurses) will be offset
by a reduced number of consultations with the general practitioner and neurologist. If these outcomes are reached,
wide implementation of PDNS care will be warranted.
(Continued on next page)

* Correspondence: [Link]@[Link]
1
Department of Neurology, Donders Institute for Brain, Cognition and
Behavior, Radboud University Medical Center, PO Box 9101 (947), 6500, HB,
Nijmegen, The Netherlands
Full list of author information is available at the end of the article

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License ([Link] which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
([Link] applies to the data made available in this article, unless otherwise stated.
Radder et al. Trials (2020) 21:88 Page 2 of 11

(Continued from previous page)

Trial registration: [Link], NCT03830190. Registered February 5, 2019 (retrospectively registered).
Keywords: Parkinson’s disease, Parkinson’s disease nurse specialist, Nursing, Quality of life, Cost-effectiveness,
Multidisciplinary care

Background status and reduce anxiety and depression [12–14], but

Parkinson’s disease (PD) is a complex, progressive neuro- definite conclusions cannot be drawn. Moreover, there is
degenerative disorder. Despite optimal medical manage- little evidence to show that quality of life actually im-
ment, such as with dopaminergic medication or deep proves with PDNS care. Finally, to date, no studies have
brain stimulation (DBS) [1], most persons with PD experi- evaluated the cost-effectiveness of PDNS care [9].
ence progressively increasing disabilities that influence the Presumably because the scientific evidence is inconclu-
quality of life of both patients and their caregivers [2, 3]. sive, many centers currently lack the nursing capacity and
PD is characterized by a wide range of motor and nonmo- financial resources to offer PDNS care to all patients. This
tor symptoms, including bradykinesia, tremor, rigidity, gait situation creates an undesirable inequality in access to
disturbances, psychiatric symptoms, and autonomic and care and presumably leads to avoidable disability and costs
cognitive dysfunction [4]. Many of these symptoms (i.e., (e.g., from early admissions to nursing homes or crisis
freezing of gait, postural instability, and a wide range of admissions to the hospital). Therefore, we aim to study
nonmotor symptoms) are poorly controlled by medication the cost-effectiveness of specialized nursing care provided
[5]. The complexity of the disease in combination with by a PDNS as compared with no PDNS care for people
limited treatment options creates tremendous challenges with PD. We hypothesize that offering PDNS care will
for the management of PD [6] and in coping with the lead to higher quality of life [15, 16]. We also expect
disease for patients and their caregivers [7, 8]. healthcare costs to remain equal, because any increases in
In primary care, improved collaboration between doc- direct medical costs (to fund the extra nurse staffing) will
tors and nurses may lead to more integrated and conse- be offset by a reduced number of (telephone) consulta-
quently better-quality care. Indeed, there is increasing tions with the primary care physician and neurologist.
evidence that care delivered by trained nurses may gener- When this hypothesis is confirmed, wide implementation
ate similar or possibly better health outcomes for a wide of PDNS care for patients with PD in all disease stages will
range of disorders [9]. For the specific situation of PD, the be warranted. Conversely, negative findings would neces-
Parkinson’s disease nurse specialist (PDNS) might fulfill a sitate a critical reappraisal of the role of PDNS care as it is
pivotal role in the multidisciplinary team. The PDNS was defined and delivered in its current form.
introduced in 1989 in the United Kingdom to bridge the
gap between medical management and the unique per- Methods
sonal needs of patients [10]. To obtain greater uniformity Study design
in care delivery and to facilitate the efficacy of nursing The Cost-effectiveness of Nursing Interventions for
care in PD, the Dutch guideline “Nursing care in Parkin- Patients With PD (NICE-PD) study protocol is re-
son’s disease” was published in 2015 [11]. The main roles ported here according to the Standard Protocol Items:
of the PDNS are clearly described in this guideline, includ- Recommendations for Interventional Trials (SPIRIT)
ing (1) providing information, education, and instruction; 2013 Statement [17]. Additional file 1 details the
(2) supporting the patient and caregiver in the promotion NICE-PD SPIRIT checklist. The study is an 18-month,
of self-management; (3) supporting psychosocial care single-blind, randomized controlled clinical trial that
questions; (4) prevention; (5) specialized diagnostic strat- will be performed in eight community hospitals in the
egies and therapeutic nursing interventions; and (6) multi- Netherlands. The participating centers are listed in
disciplinary collaboration. Table 1. A total of 240 people with PD will be included
Based on expert opinion from healthcare professionals, (120 in each group), equally distributed over the par-
the Dutch guideline recommends that every person with ticipating hospitals. We have selected hospitals where,
PD could benefit from PDNS care, including those in due to lack of sufficient PDNS staff, only a proportion
early-stage disease, where information delivery, educa- of patients with PD currently have access to PDNS
tion about medication compliance, and support in self- care. This provides us with a unique opportunity to
management are crucial. So far, only three studies have identify patients who currently have no access to PDNS
evaluated PDNS care, with inconsistent results. Overall, care and to randomize them within hospitals (at the
the findings suggested that PDNS care may improve pa- patient level) to PDNS care or to no nursing interven-
tient well-being, physical functioning, and general health tion. We summarize the study design in Fig. 1. The
Radder et al. Trials (2020) 21:88 Page 3 of 11

Table 1 Participating community hospitals in the Netherlands perform the clinical assessments at baseline (t0), after 12
Center Location months (t1), and after 18 months (t2). Patients and care-
BovenIJ Hospital Amsterdam givers will also be asked to complete a set of question-
Treant Care Group, location Scheeper Emmen
naires at t0, t1, and t2. Finally, every 3 months, patients
and their caregivers will complete a questionnaire about
Elisabeth-TweeSteden Hospital Tilburg
healthcare utilization, costs, and productivity loss. Care
St. Jans Gasthuis Weert providers (e.g., neurologists) will not be blinded to the
Máxima Medical Center Veldhoven assigned interventions. We do not foresee any reason why
Rode Kruis Hospital Beverwijk unblinding of participants would be necessary.
Dijklander Hospital Purmerend
Zaans Medical Center Zaandam
Inclusion and exclusion criteria
The inclusion and exclusion criteria for patients are kept
enrollment and assessments during the study period purposefully broad in order to represent the full diversity
are shown in Fig. 2. of the PD spectrum and thus generate results that apply
Eligible patients will be allocated randomly to either to real clinical practice. All patients with PD, regardless of
PDNS care or usual care in a 1:1 ratio, using a computer- disease severity or disease duration, male and female, aged
generated list of random numbers. An independent 18 years or older at the time of PD diagnosis are eligible.
researcher (who will not perform study assessments) will We will only exclude patients for the following reasons:
perform the randomization using an online data manage-
ment system. Subsequently, this researcher will contact  Lack sufficient knowledge of the Dutch language to
the PDNSs to inform them about which participants are complete questionnaires
randomized to the intervention group. The other partici-  Have received care from a PDNS in the past 2 years
pants will receive a letter or an e-mail stating that they  Have a score < 18 on the Mini Mental State
have been assigned to the control group. To ascertain an Examination [18] and < 12 on the Frontal
equal representation of patients, we will stratify for gender Assessment Battery [19]
and disease duration (according to predefined subgroups;  Have a type of atypical parkinsonism caused by
i.e., disease duration < 5 years, 5–10 years, and > 10 years). medication (e.g., neuroleptics), a metabolic disorder (e.g.,
The PDNS intervention will follow the Dutch guideline Wilson’s disease), encephalitis, or a neurodegenerative
“Nursing care in Parkinson’s disease” [11] (see the “PDNS disorder (e.g., multiple system atrophy, progressive
intervention” section below). A blinded researcher will supranuclear palsy, corticobasal syndrome)

Fig. 1 Summary of the study design. *Time points for clinical assessments. PDNS Parkinson’s disease nurse specialist
Radder et al. Trials (2020) 21:88 Page 4 of 11

Fig. 2 Example template of recommended content for the schedule of enrollment, interventions, and assessments

 Residing in a nursing home or another type of (where the PDNS and neurologist are also present).
residential care facility (because the PDNS is not Here, the patient information letter will be handed
operational there) out directly. Importantly, patients will be given
 Have any other medical or psychiatric disorder that, sufficient time to consider their participation. If
in the opinion of the researcher, may compromise they are interested, they will be contacted by the
participation in the study research team at least 2 weeks after the information
session.
Recruitment
Patients will be approached within each hospital using Training and coaching of Parkinson’s disease nurse
one of three scenarios: specialists
Before the start of the study, we will organize a single
1. The involved neurologists in the hospitals identify training session with all participating PDNSs (one from
eligible patients from their electronic patient file each center). The goal of this meeting is to acquire
and inform these patients about the study in their commitment to the study and uniformity in workflow by
clinic (when the patient is coming in for a reviewing the “Nursing care in Parkinson’s disease” guide-
consultation). A patient who agrees to be line to explain the study specifics and to discuss practical
approached by a researcher will be provided with issues related to the study intervention. In addition,
the patient information letter. PDNSs will be closely coached in order to optimize the
2. The neurologists identify eligible patients using intervention and adherence to the guideline. Every month,
their electronic patient file and subsequently an experienced PD nurse from Radboudumc will have an
approach them by directly sending out a letter individual intervention session with each PDNS, mainly to
including a short description of the study and a discuss difficult cases and to optimize the intervention
form on which patients can indicate if they want to and its uniformity. Finally, we will organize a video meet-
receive any further information about the study or ing every 3 months with all PDNSs to maintain their com-
not. Only if patients actively indicate that they wish mitment, support each other, discuss difficulties related to
to be approached will the researcher contact them the study, and give each other advice [20, 21].
by telephone and send them the information letter. Importantly, for the purpose of this study, we will
3. The research team organizes an information implement an increase in nursing staff capacity for
meeting for patients in the participating center participating nurses. This will allow us to study the real
Radder et al. Trials (2020) 21:88 Page 5 of 11

impact of current usual care, which would not be Table 2 Specific nursing interventions according to the Dutch
achieved by adding a new set of specifically trained re- guideline for nursing care in Parkinson’s disease that are also
search nurses to the existing PDNS staff. The PDNSs are reminiscent of the Fundamentals of Care Framework
all graduated nurses (education level according to the Area Interventions
European Qualifications Framework 6 or 7) with a cer- Mental Providing information and education
tificate in Parkinson’s nursing. Furthermore, they have function Activation and supporting the creation of a day structure
Supporting the caregiver
achieved a standard of competence as described in the
“Nursing care in Parkinson’s disease” guideline [11]. Fatigue Supporting the intake of food with sufficient caloric
value
Promoting physical exercise
PDNS intervention Structuring daily activities
The PDNS intervention will be performed according to Sleep Providing sleep hygiene advice (e.g., no alcohol or
the Dutch “Nursing care in Parkinson’s disease” guide- caffeine before sleep, no watching television or using the
computer before sleep)
line published in 2015 [11]. The intervention is not stan- Changing medication in consultation with the
dardized but tailored to the patients’ and caregivers’ neurologist in case of nocturnal on/off fluctuations
needs. This includes the following: Urogenital Advising to drink 1.5–2.0 L of fluid per day
functions Advising the reduction of fluid intake before sleep
 Assessment of individual care needs of people with Advising the intake of food rich in fibers
PD and their caregivers: At the start of the study, Sexuality Providing information and education
the PDNS performs a specific nursing assessment Providing specific advice according to the type of sexual
dysfunction (e.g., reduced sexual desire, erectile
related to the medical, physical, psychological, and dysfunction)
social domains. Medication Providing information and education about the timing
 Development of a patient-centered treatment plan adherence and intake of medication (e.g., with water, not with milk)
that supports the patient and caregiver in self- Stimulating medication adherence
management: The PDNS composes a Orthostatic Advising to wear support stockings
multidisciplinary plan based on the results of the hypotension Advising to have sufficient salt and fluid intake per day
Providing advice about postural changes
individual assessment and as prioritized by the
patient and caregiver (shared decision making). The Caregiver Providing information and education
burden Refer the caregiver for cognitive behavioral therapy
treatment plan is developed according to the Refer the caregiver to a Parkinson’s disease-specific
national self-management framework [22]. support group
 Specific nursing interventions: The intervention Coping Advising mindfulness training
varies across disease stages and is tailored to the Supporting patients and caregivers to view problems
from different perspectives to develop new strategies for
specific problems and needs of individual patients solving these problems
and their caregivers. The “Nursing care in Refer for cognitive behavioral therapy
Parkinson’s disease” guideline for care describes Mobility Applying cognitive movement strategies
general and specific nursing interventions. General Applying external cues
interventions consist of providing information and Stimulating the patient to perform sufficient
physical exercise
education, disease management (e.g., considering
advanced treatment options such as DBS), and Self- Stimulating the patient to ask questions
management Providing individualized patient-related information
monitoring (e.g., of caregiver burden). Specific Asking if the provided information matches the
nursing interventions are described for the following patient’s question
areas: mental function, fatigue, sleep, urogenital Dietary Providing information and education about problems
functions, sexuality, medication adherence, issues with food absorption (e.g., because of the interaction
with protein intake)
orthostatic hypotension, caregiver burden, coping, Preventing accidental weight loss
mobility, self-management, and dietary issues. Providing advice about oral care
(Table 2 provides examples of such interventions.) Dutch guideline for nursing care in Parkinson’s disease [11]; Fundamentals of
 Collaboration with other healthcare professionals. Care Framework [23]. Note that this list is not exhaustive
The PDNS stimulates and supports multidisciplinary
collaboration between healthcare professionals based
on the individual patient-centered treatment plan.
The PDNS also plays a pivotal role in timely referral with PD, documenting the individual care needs, current
to other healthcare professionals. symptoms, performed interventions, and (changes in)
the individual care plan. This report will be started at
The PDNS will maintain a predefined electronic study the initial assessment and updated at every follow-up
report according to a structured format for each patient contact with the patient, such as at the outpatient clinic,
Radder et al. Trials (2020) 21:88 Page 6 of 11

during a telephone consultation, or at a home visit. This on DBS [42] and multidisciplinary care [43]. Our second
information will be purposefully collected for a possible co-primary outcome measure is the severity of motor
process analysis at the end of the study. symptoms measured by the MDS-UPDRS part III. The
Patients will have regular contact with their PDNS MDS-UPDRS is a frequently used clinical rating scale
about the progress and realization of the personal goals, and has been shown to be sensitive to change in clinical
both during face-to-face contacts and by telephone, and status [44]. Both scales have been validated previously
sometimes during additional home visits. The frequency and are reliable and valid methods to measure either
and type of contact will be optimized for each patient, de- quality of life [45] or motor symptoms [46] in people
pending on disease stage and individual patient needs. The with PD.
“Nursing care in Parkinson’s disease” guideline advises that
each patient have a minimum of one contact with the Data collection and management
PDNS each year [11]. Currently in the Netherlands, patients Patients will be given a unique personal identification
are seen, on average, twice annually by their PDNS, with an code not containing any information that refers back to
additional two interim telephone consultations per year. the individual. The key file connecting personal identifi-
The control group will receive ongoing usual care cation codes to the individual patient will be stored on a
that is medically comparable to that in the intervention secure Radboudumc data server. Only the research team
group, but without a nursing intervention. This involves has access to this key. The key file will be stored on a
regular consultations with a neurologist in their own different server from the one with acquired study data
community hospital (typically two to four times per for 5 years, allowing the research team to contact
year, depending on patient preferences and health sta- patients after they have finished the study. After 5 years,
tus). In addition, control patients will have no restric- the key file will be destroyed.
tions when considering any other medical treatments Data from all paper-based case report forms (CRFs) com-
(e.g., by a psychologist or social worker). Importantly, pleted by the researcher (PDQ-39, MDS-UPDRS, and
many key elements of care (including in particular the TUG) will be entered manually into an online certified data
treating neurologist) remain comparable between the management system (Castor EDC; Castor, Amsterdam, the
two arms because of the randomization at the patient Netherlands). Online CRFs (the remaining questionnaires)
level within hospitals. will automatically be recorded in Castor EDC. When pa-
tients or caregivers are not able to complete questionnaires
Clinical assessment and outcome measures online, they also have the opportunity to do this on paper.
At baseline, t1, and t2, all patients will visit their own We will send out the questionnaires by post, and patients
hospital for the study assessments, which are performed can return the completed questionnaires using a self-
by a blinded researcher (Parkinson’s Disease Question- addressed envelope. These questionnaires will be entered
naire [PDQ-39], Movement Disorders Society-sponsored manually into Castor EDC. Both online and paper-based
revision of the Unified Parkinson’s Disease Rating Scale CRFs only contain the personal identification code.
[MDS-UPDRS], and Timed Up and Go test [TUG]). The Clinical notes taken by the PDNS in the online study
patients and their caregivers will also complete home report will also not contain any information that refers
questionnaires. In addition, every 3 months, patients will back to the individual. PDNSs are instructed to make
receive a questionnaire at home regarding healthcare notes according to a predefined structured format with-
utilization, costs, and productivity loss over the past 3 out mentioning personal information that traces back to
months. Caregivers will complete a cost questionnaire, an individual patient. The study report will be completed
including healthcare utilization, costs, and productivity in Castor EDC.
loss, specifically related to caregiver burden. To improve
adherence, patients and caregivers can choose whether Adverse events
they prefer to fill out digital or paper-based question- All serious adverse events (SAEs) will be collected and
naires. Participants will be contacted by telephone when followed up by the investigators and documented in the
they do not complete the questionnaires within 4 weeks. electronic CRFs. Each SAE will be reported by the re-
All the outcomes, including secondary outcome mea- spective PDNS to the study team (DR), and the SAE will
sures, can be found in Table 3. be reported to the local ethics committee as soon as the
Similar to previous large randomized controlled trials researcher has knowledge of the SAE, but no later than
in the field of PD [39, 40], we will use two co-primary 24 h after the researcher has become aware of the event.
outcomes: quality of life and motor symptoms [41]. For Other adverse events will not actively be inquired for
measuring quality of life, we will use the PDQ-39, which during the study, because of the low risk associated with
is the most widely used quality-of-life scale in PD and the trial. When a participant spontaneously reports an
frequently used as an outcome measure, such as in trials adverse event, it will be registered in the electronic CRF.
Radder et al. Trials (2020) 21:88 Page 7 of 11

Table 3 Outcome measures used at different time points

Outcome Questionnaire Baseline 12-month 18-month Every 3
follow-up follow-up months
Co-primary outcome measures
Quality of life Parkinson’s Disease Questionnaire (PDQ-39) [24] X X X
Motor symptoms Movement Disorders Society-sponsored revision X X X
of the Unified Parkinson’s Disease Rating Scale
part III (MDS-UPDRS part III) [25]
Secondary outcome measures
(patient-related)
Longitudinal PD symptoms Movement Disorders Society-sponsored revision X X X
of the Unified Parkinson’s Disease Rating Scale
parts I, II, and IV (MDS-UPDRS parts I, II, and IV) [25]
Mobility Timed Up and Go (TUG) [26] X X X
Nonmotor symptoms (anxiety Hamilton Anxiety and Depression Scale (HADS) [27] X X X
and depression)
Nonmotor symptoms (e.g., sleep, Scales for Outcomes in Parkinson’s X X X
incontinence, constipation) Disease–Autonomic Questionnaire and Sleep
Questionnaire (SCOPA-AUT) [28], SCOPA-SLEEP [29]
Health-related quality of life EuroQoL-5D (EQ-5D) [30] X X X
Experienced quality of care Consumer Quality Index (CQI) [31] X X X
Self-management Patient Activation Measure (PAM13) [32] X X X
Medication adherence Morisky Medication Adherence Scale (MMAS) [33] X X X
Secondary outcome measures
(caregiver-related)
Health-related quality of life EuroQoL-5D (EQ-5D) [30] X X X
Caregiver burden [24] Zarit Caregiver Burden Index (ZBI) [34] X X X
Caregiver quality of life CarerQol-7D [35] X X X
Skills of proactive coping Utrecht Proactive Coping Competence Scale X X X
(UPCC) [36]
Healthcare utilization, costs, and
productivity loss
Medical consumption of Medical Consumption Questionnaire (MCQ) [37] X
the patient
Productivity loss of the patient Productivity Cost Questionnaire (PCQ) [38] X
Medical consumption of the Medical Consumption Questionnaire (MCQ)
caregiver related to caregiver burden specifically adapted for andaimed at caregivers [37]
Productivity loss of the caregiver Productivity Cost Questionnaire (PCQ) specifically X
related to caregiver burden adapted for and aimed at caregivers [38]
PD Parkinson’s disease

Sample size analysis endpoints: PDQ-39 and MDS-UPDRS part III) and a
We performed a sample size calculation based on the power of 80%, a sample of 93 patients in each group
PDQ-39 score. On the basis of observations in one of would be needed. Considering an attrition rate of 20%,
our previous studies in a similar population of patients 117 patients are needed per group. We have rounded
with PD where we evaluated multidisciplinary care [43], this up to 120 patients per group, which means a total of
we found a mean improvement in PDQ-39 score in the 240 patients. We expect this to be feasible because fol-
intervention group of − 2.5 (SD, 5.8) points and a mean lowing a baseline inventory, all centers indicated that
deterioration in PDQ-39 score in the control group of + they would be able to include at least 30 patients.
1.4 (SD, 8.6). We calculated the sample size based on a
mean difference between groups of 3.9, with an SD of Data analysis
8.6 (the highest SD reported). Using a significance level The economic evaluation investigates, alongside the clin-
of alpha = 0.025 (instead of 0.05 because of two primary ical trial, the value for money of full implementation of
Radder et al. Trials (2020) 21:88 Page 8 of 11

the PDNS into PD care from a societal and healthcare Trial oversight
perspective. We will take all relevant costs into account. The chief investigator has the overall responsibility for
The cost-effectiveness time frame adheres to the clinical the conduct of the study. The study group has responsi-
study protocol and evaluates cost-effectiveness up to 18 bility for the day-to-day management of the trial and
months after randomization. Cost will be measured using a consists of the following authors: DLMR, HHL, RHH,
healthcare utilization questionnaire (e.g., including medical MM, NMdV, and BRB, who designed the study. DLMR
consultations, hospital admissions, medication, travel costs) and NMdV are responsible for day-to-day management
and a questionnaire measuring productivity loss while of the trial, including the inclusion of participants and
working of both patients and caregivers. Per item of health- communication with participating centers, participants,
care consumption, standard cost prices will be determined and the ethics committee. TvA, CCSD, and HV have a
using the guideline for performing economic evaluations more consultative role and provide substantial feedback
[47]. If standardized prices are not available, full cost prices regarding the trial procedures. There will be no inde-
will be determined using activity-based costing. Costs will pendent data monitoring committee, owing to the low
be analyzed using a mixed model approach or a general lin- risk associated with the trial. The results of the study
ear model approach with a gamma distribution using a log will be sent for publication to a peer-reviewed medical
link to account for possible skewness of the cost data. journal. No professional writers will be involved. In
We will use a PD-specific quality of life measure addition, the results will be shared with trial participants
(PDQ-39) and a generic health-related quality of life via the Dutch Parkinson Association and via Parkinson-
scale (EQ-5D) to evaluate the quality of the health status Net. We report no restrictions for publication.
of patients. The potential difference in quality-adjusted
life-years measured with the EQ-5D will be analyzed Discussion
with a regression approach. We will use a linear mixed Here, we present the rationale and design of the NICE-PD
model with repeated measurements to test for differ- study, a large (n = 240) randomized controlled clinical trial
ences in quality of life (measured with the PDQ-39) be- that aims to evaluate the cost-effectiveness of specialized
tween both groups. The same analysis will be used to nursing interventions provided by a PDNS for people with
measure differences between groups in the secondary PD. The results of this trial will have an immediate impact
outcome measures. We will include study center as a on current care for people with PD, independent of its
random effect and fixed effects for group, time, and the outcome. When the intervention is shown to be cost-
interaction between group and time. Each of the out- effective, a wider implementation of PDNS care for all pa-
comes will be included as a dependent variable. Statis- tients will be warranted. This requires an increase in PD
tical analyses will be performed on the basis of the nursing capacity, which means that further efforts must
intention-to-treat principle. then be initiated to ensure that policy makers and payers
As mentioned previously, we hypothesize that both in- will invest in the reimbursement of PDNS care. We expect
terventions (PDNS care versus no PDNS care) will yield that investment in extra PDNS capacity will not lead to a
equal costs, while PDNS care is more effective. If this net increase in costs, because the number of neurologist
hypothesis is confirmed, then the effect analysis is suffi- consultations may decrease proportionally to the increas-
cient to show the efficiency of PDNS care. The design of ing PDNS care. On the other hand, if cost-effectiveness is
the economic evaluation follows the principles of a cost- not shown, current guideline recommendations should be
effectiveness analysis and adheres to the Dutch guideline reevaluated critically, and a discussion should be started
for performing economic evaluations in healthcare [47]. on how PDNS care delivery should be modified for it to
Besides the overall cost-effectiveness evaluation, we be more effective. One may also argue that PDNS care
will perform a preplanned subgroup analysis based on could be considered successful when quality of life signifi-
disease duration (diagnosis made < 5 years, 5–10 years, cantly improves with a slight increase in costs. With this
or > 10 years ago) to obtain more insight into the nursing outcome, it may be worth investing in PDNS care to fur-
interventions used in each disease stage and the effects ther improve the quality of life of people with PD and to
of PDNS care in these different groups of patients. This search for solutions to optimize efficiency and reduce
subgroup analysis will be performed because, for ex- costs of PDNS care interventions.
ample, for the more severely affected patients, the We hypothesize that offering PDNS care will lead to
nursing intervention is expected to become more in- higher quality of life with equal healthcare costs. Increas-
tensive and possibly more effective but also more ex- ing direct medical costs (for nurse staffing) are expected
pensive. When different patterns of this kind are to be offset by a reduced number of (telephone) consul-
found, this should be investigated further in future tations with the general practitioner and neurologist.
trials that are powered adequately to address such These short-term goals are the focus of the present
group differences. NICE-PD proposal. In addition to the short-term
Radder et al. Trials (2020) 21:88 Page 9 of 11

effects, we also expect long-term benefits, but these outcome measures. To accommodate this, we have chosen
are beyond the scope of the current project. Examples more cautious levels of statistical significance. Moreover,
of potential long-term benefits include a reduction in the study was powered for a single outcome (quality of
the number of nursing home admissions and fewer life), but the study’s power is sufficient to also detect a
emergency visits to the hospital, which could poten- minimal clinically important difference for the co-primary
tially lead to a substantial cost reduction. outcome (the MDS-UPDRS). The reason why we expect
This is the first randomized controlled clinical trial to an improvement in this other primary outcome is because
evaluate the cost-effectiveness of PDNS care. However, when patients receive more integrated care, their motor
this study is not without challenges. During the study symptoms may also improve.
period, each hospital receives extra budget (out of the In conclusion, this study will generate new insights into
grant money) to increase their PDNS capacity for pro- the cost-effectiveness of specialized PD nursing interven-
viding better care to the patients in the intervention tions for people with PD. If positive results are found, a
group. However, this reimbursement cannot be contin- large shift in the organization of PD care is needed to war-
ued after the study has ended. It will be a challenge to rant equal access to PDNS care for every person with PD.
offer continuity of care for the participating patients
when nursing capacity has to be reduced again after the
Trial status
study because of a reduction in funding. We hope that
Protocol version 3, date: April 8, 2019. Recruitment started
positive results of the present study will provide a strong
on January 7, 2019, and is currently ongoing. The expected
impetus for identifying the necessary financial resources
date for recruitment completion is December 2019.
to finance sufficient nursing capacity in the long term.
To ascertain this, we will engage in discussions with
Dutch payers already at the outset of the study. The sec- Supplementary information
ond challenge is that the patients in the control group Supplementary information accompanies this paper at [Link]
1186/s13063-019-3926-y.
will not have access to PDNS care during the complete
study period. However, there are no restrictions on other Additional file 1. The NICE-PD SPIRIT 2013 checklist.
medical treatments, which means that the control pa-
tients are allowed to consult all other available health-
care providers (e.g., physiotherapists, psychologists, and Abbreviations
CONSORT: Consolidated Standards of Reporting Trials; CRF: Case report form;
social workers). There are two exceptions, though, in DBS: Deep brain stimulation; MDS-UPDRS: Movement Disorders Society-
which care by a PDNS will only be directed at these spe- sponsored revision of the Unified Parkinson’s Disease Rating Scale; NICE-
cific situations: (1) providing specific information and PD: Cost-effectiveness of Nursing Interventions for Patients With
PDPDParkinson’s disease; PDNS: Parkinson’s disease nurse specialist; PDQ-
guidance about advanced therapies (e.g., DBS, duodopa 39: Parkinson’s Disease Questionnaire; SAE: Serious adverse event;
infusion) and (2) moral dilemmas in crises (e.g., psych- SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials;
osis). Note that a group of patient researchers who were TUG: Timed Up and Go
involved in the design of this NICE-PD study consider it
ethically acceptable to deny these patients access to Acknowledgements
Not applicable.
PDNS care during a period of 18 months because we are
not withholding an evidence-based treatment (current
Authors’ contributions
evidence is limited). This is because patients were not DLMR designed the study and drafted and revised the manuscript. HHL
receiving any PDNS care anyway outside the study and designed the study and revised the manuscript. HV provided substantial
because we can now exploit this situation to gain scien- feedback on the design of the study and revised the manuscript. TvA
provided substantial feedback on the design of the study and revised the
tific evidence about the cost-effectiveness of PDNS care. manuscript. CCSD provided substantial feedback on the design of the study
This new knowledge will eventually benefit all patients and revised the manuscript. RHH designed the study and revised the
with PD, including those allocated to the control arm of manuscript. MM designed the study and revised the manuscript. BRB
designed the study and revised the manuscript. NMdV designed the study
the present trial. and drafted and revised the manuscript. All named authors read and
Third, because PDNSs are not operational in nursing approved the final manuscript. All authors adhered to the authorship
homes or other types of residential care facility, it may be guidelines of Trials. No professional writers have been involved.
more difficult to include severely affected patients in this
study. We will try to overcome this by stratifying for dis- Funding
This is an investigator-initiated study in which the sponsor and funders have
ease duration and by carefully selecting patients in all dis- no roles in the study design or the collection, management, analysis,
ease stages from each center. Finally, because quality of interpretation, and reporting of data. This work was supported by a research
life is a very generic outcome measure, it may be a chal- grant from ZonMw (The Netherlands Organisation for Health Research and
Development) and Zambon. The Radboud University Medical Centre, Geert
lenge to find relevant results on this metric. To overcome Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands, is the sponsor of
this challenge, we have chosen to use two co-primary the study. Telephone number: 003124-361-1111.
Radder et al. Trials (2020) 21:88 Page 10 of 11

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