3.1 Study description
The NA-CONTROL study is the first randomised controlled trial investigating treatment for residual complaints in neuralgic amyotrophy. It additionally investigates a relatively unexplored concept (i.e. the role of (mal)adaptive cerebral neuroplasticity in a disorder of the peripheral nervous system) and employs techniques (including functional MRI) that have not yet been used to study the underlying cerebral mechanisms of NA. This study is conducted at the Donders Institute for Brain Cognition and Behaviour and the departments of Rehabilitation and Neurology of the Radboudumc in Nijmegen, the Netherlands.
In this two-arm, single-centre, open-label, randomised controlled trial (RCT), the effect of a rehabilitation program on functional capability and motor planning of the upper extremity is compared to that of usual care. The intervention group will receive a specific 17-week multidisciplinary rehabilitation program at the Radboudumc outpatient clinic, focused on relearning motor control and self-management (see Intervention under 3.7 for more information). The usual care group will first receive usual care, for a 17-week period, before entering the rehabilitation program.
Patients in both groups will be assessed in a single session at baseline. At the end of the baseline measurement, patients will be randomised into the intervention or usual care group (see randomisation for more information). After the first 17 weeks of treatment (i.e. rehabilitation program or usual care), both groups will be assessed in a second session (at 18 weeks post baseline). After this second assessment, the group that initially received usual care will then follow the specific rehabilitation program. After completing the 17-week rehabilitation program, the usual care group will be assessed a third time (at 36 weeks post baseline). All patients will be asked to fill out several questionnaires through e-mail 17 weeks after completing the rehabilitation program. This follow-up will be at either 36 weeks (intervention group), or 54 weeks (usual care group) post baseline.
The baseline measurements of all NA patients for the randomised controlled trial described in this publication (see Figure 2) will be used for a sub-study. In this sub-study, NA patients will be compared to 25 age- and sex-matched healthy controls. The healthy controls are assessed in a single session. The primary objective of this sub-study will be to determine if NA patients have altered cerebral activity related to motor planning of their affected arm compared to healthy controls and compared to their non-affected arm. This sub-study is important for the interpretations of the secondary objective (the effect of this rehabilitation program on cortical motor planning and representations), to provide information about which cerebral changes from the rehabilitation program are associated with functional impairments in NA.
3.2 Study population
NA is more prevalent in men than in women, with an incidence ratio of 2:1, and can affect people of all ages. NA has an idiopathic form, with a median age of onset around 40 years and a hereditary form with a median age of onset of about 28 years (7, 9). Patients that are 18 years or older, with either form of NA can participate.
3.2.2 Inclusion criteria
The treating rehabilitation physician or his/her physician assistant will judge whether a potential participant meets the inclusion criteria. In order to be eligible to participate in this study, a participant must meet all of the following criteria:
1. (suspected) Diagnosis of NAa
2. NA predominantly present in the right upper extremity
3. Being in the subacute or chronic phase of NA (i.e. no inflammation of the plexus, in practice: >8 weeks after attack onset)
4. Presenting with scapular dyskinesia
5. Age ≥ 18 years
6. Right-hand dominance (as indicated with an Edinburgh Handedness Inventory (EHI) score of > +40)
7. Able to provide informed consent
a Initially, the (suspected) diagnosis of NA will be deduced from the information in the referral letter from the patient’s referring general physician or neurologist. If any uncertainty about the diagnosis remains, the rehabilitation physician or his/her physician assistant will contact the referring physician and/or patient. All patients will visit the specialised outpatient clinic, where the diagnosis will be either confirmed or discarded.
3.2.3 Exclusion criteria
For the NA patients, the treating rehabilitation physician or his/her physician assistant will judge whether a potential participant meets one or more of the exclusion criteria. A potential participant who meets any of the following criteria will be excluded:
1. Prior NA attacks of the lumbosacral plexus or the left upper extremity
2. Previously participated in the specific rehabilitation program offered at the Radboudumc or rehabilitation centre KINOS
3. Other neuromuscular disease affecting the shoulder girdle
4. Central nervous system disorder or neurological disorder (e.g. Parkinson disease, stroke etc.)
5. Pre-existing (bio)mechanical constraints of the shoulder girdle
6. A history of, or recent periarticular fractures of the shoulder
7. Past surgery of the shoulder
8. Depressive mood disorder, as indicated by a score of >5 on the Beck Depression Inventory Fast Screen (BDI-FS)
9. Severe comorbidity
10. Ongoing participation in another scientific study that might interfere with the current study
For undergoing the MRI scans:
11. Pregnancy (current or planned within the study period)
12. The presence of metal parts, that cannot be removed, in or on the upper body (including; plates, screws, aneurysm clips, metal splinters, piercings, medical plasters, or ossicle prosthesis. Exception: dental fillings or crowns)
13. The presence of an electric implant (e.g. pacemaker, neurostimulator, insulin pump)
14. A history of brain surgery
3.2.4 Participant selection and enrolment
Figure 3 provides a flow-chart of the recruitment, consent, and other procedures of patients in the NA-CONTROL study.
22.214.171.124 Identifying potential participants
All NA patients that are newly referred to the Muscle Center of the Radboudumc during the study’s inclusion period will be checked for eligibility (i.e. meeting inclusion criteria 1 through 5) by a member of the treatment team through evaluation of the referral information. Eligible patients are informed about the NA-CONTROL study and their eligibility through written mail. At least a week after this notification letter is sent, a member of the treatment team will contact the patient to ask for his/her consent to be contacted by the coordinating researcher. If a patient expresses interest and provides consent, (s)he will receive the extensive trial information package via (e-)mail.
126.96.36.199 Consenting participants
The coordinating researcher will contact patients that consent 7-14 days after the extensive trial information has been sent. After providing further clarification if needed, the coordinating researcher will state the in- and exclusion criteria. If a patient indicates that (s)he meets the in- and exclusion criteria, the researcher will ask the patient for oral consent and the baseline measurement will be scheduled.
Written informed consent will be obtained prior to the start of the baseline measurement by the coordinating researcher at the research location. All participants will receive a copy of the signed informed consent form. The original signed informed consent forms will be kept at the study site. After written informed consent is obtained, the patient’s hand dominance will be determined with the EHI (15) and the patient will be screened for signs of depressive mood disorder with the Beck Depression Inventory-Fast Screen (see inclusion criterion 6 and exclusion criterion 8, respectively).
Patients’ participation will be noted in their medical chart. As per national regulations, for all participants, the general practitioner will be notified of their participation.
188.8.131.52 Ineligible and non-recruited patients
Patients’ decision to decline participation will in no way affect their treatment at the Radboudumc. This is clearly communicated to patients during all contacts. For patients who are not eligible, who express that they are not interested in participation, or who do not meet all in- and exclusion criteria, the usual procedure is followed; they will be put on the regular waiting list for a consultation at our expert outpatient clinic. The content of the rehabilitation program is the same for patients that participate in the trial as for those that receive the rehabilitation program outside the study.
See Table 1 for an overview of all outcome measures and their corresponding time points of collection.
Functional capability of the upper extremity
The primary outcome measure for the clinical part of the RCT is the change in SRQ-DLV score from baseline to post-intervention. The SRQ-DLV is a reliable and validated questionnaire measuring functional capability of the shoulder, arm and hand (16) and has been shown to be sensitive to (changes in) functional capability of the shoulder in NA patients (14).
3.3.2 Secondary outcomes
Secondary outcome measures are divided in clinical measures and measures related to motor planning (see below).
The secondary clinical outcome measures cover multiple domains of the International Classification of Functioning, Disability and Health (17):
A. Activities and function
To assess activities and function, the following additional questionnaire is administered:
a. Disability of Arm, Shoulder and Hand (DASH)
The DASH questionnaire measures the functional capability of the affected upper extremity and has good clinimetric properties (18).
B. Personal factors
Fatigue, pain, self-efficacy, and patient activation are assessed with the following questionnaires:
a. Checklist individual strength - subscale fatigue (CIS-fatigue)
The CIS-fatigue measures experienced fatigue (19).
b. McGill Pain Questionnaire (MPQ)
The MPQ measures experienced pain. It assesses the nature, intensity, location, course, and effect on daily life of the pain (20).
c. Self-efficacy for performing energy conservation strategies assessment (SEPECSA)
The SEPECSA assesses how the patients perceive their ability to apply energy conservation strategies to their daily lives (21).
d. Pain self-efficacy questionnaire (PSEQ)
The PSEQ assesses the confidence that people with ongoing pain have in performing activities while being in pain (22).
e. Patient activation measure (PAM)
Patient’s activation with regard to their health and disease is assed with the PAM. The PAM measures knowledge, skills and confidence in managing one’s own health and/or disease (23).
Participation is assessed with the following measures:
a. Utrecht scale for evaluation of rehabilitation-participation (USER-P)
The USER-P is used to evaluate the effect of outpatient rehabilitation on participation (24).
b. Canadian Occupational Performance Measure (COPM)
The COPM is used to evaluate occupational performance and satisfaction with performance of the most important daily occupations identified as problematic by the patient. It thus assesses occupational participation (25). The COPM is administered during the first and last sessions of the specific rehabilitation program (14). These assessments will serve as a pre- and post-intervention comparison within NA patients that underwent the experimental intervention.
D. Body functions
Within the body functions domain, we will assess the reachable workspace and several muscles/muscle groups
a. 3D-Reachable workspace
Reachable workspace is an objective measure of upper extremity impairment (26). It is quantified by the relative 3 dimensional surface area representing the portion of the unit hemisphere that is covered by the hand movements made during a standardised movement protocol (26). The movement protocol covers cardinal movements of the shoulder and is performed in front of the Microsoft Kinect sensor-based reachable workspace analysis system (26).
The following strength measurements will be performed to determine maximal force exerted with several muscles/muscle groups on both sides (left and right upper extremity):
b. The serratus anterior muscle
Measured with MicroFET2®, digital manual muscle dynamometer, with the arm lifted to shoulder level, in the scapular plane while:
i. Reaching with an extended arm
ii. Reaching with a flexed arm (elbow at 90°)
c. Rotation of the shoulder
Measured with MicroFET2®, digital manual muscle dynamometer, with the arm at 0° anteflexion, elbow flexed at 90°, and thumb pointing upwards
d. Hand grip
Measured with Jamar® Hydraulic Hand dynamometer, with the arm at 0° anteflexion, elbow flexed at 90°, and straight wrist
e. Pinch grip
Measured with Baseline® LiTE Hydraulic Pinch Gauge,with the arm at 0° anteflexion, elbow flexed at 90°.The pinch gauge is held between the index finger (top) and thumb.
f. Key grip
Measured with Baseline® LiTE Hydraulic Pinch Gauge, with the arm at 0° anteflexion, elbow flexed at 90°.The pinch gauge is held between the thumb (top) and index finger (bottom).
E. Quality of life
Quality of life will be assessed with:
a. Short-form 36 (SF-36)
The SF-36 assesses experienced health and health related quality of life (27).
184.108.40.206 Motor planning
Motor planning will be assessed with a motor imagery task during which functional MRI signal is recorded. Motor imagery involves mental simulation of a movement, without actual execution of that movement. It can be used as a tool to generate cortical motor states without movement production. As is evident by the presence of scapular dyskinesia, peripheral motor control is altered in NA. With motor imagery, changes in central motor control can be assessed, while controlling for alterations in peripheral factors. Empirical evidence shows that first person motor imagery tasks are sensitive to motor control variables and use central neural mechanisms involved in action planning (28-30).
a. Motor imagery task-based functional MRI
Changes (as the result of rehabilitation and as the result of NA (assessed in the sub-study) in the neural mechanisms underlying motor planning and representations will be quantified by changes in the magnitudes of mean functional MRI signal, blood-oxygen-level dependent (BOLD) activity associated with motor imagery during the Hand Laterality Judgment task (HLJT) (see b.).
Analyses of the functional MRI data will primarily be focused on the following brain regions: the extrastriate body area, the posterior parietal cortex in the intra-parietal sulcus region, and the pre- and postcentral gyri. These a priori regions of interest for analysis of functional MRI magnitude differences are chosen based on previous research using the same motor imagery task (1, 28, 30-32). Additionally, we will employ a whole brain exploratory analysis of functional changes in NA outside these canonical motor imagery regions (see also 3.3.4 Exploratory Outcomes).
Participants’ respiration will be recorded during the functional MRI scan to be able to control for noise introduced in the data.
b. Performance on motor imagery task
The HLJT (33) assesses central representations and planning of movements involving the upper extremity. Participants are asked to judge the laterality of line drawings of hands. The hands vary in laterality (left or right), view (palmar or dorsal), and degree of rotation (rotated -135°, -105°, -75°, -45°, 45°, 75°, 105°, 135° from upright position). Participants are instructed to use their own hands as reference (i.e. imagine moving their upper extremity to match the hand shown on screen), without actually moving their upper extremity. As participants perform this task in the MRI scanner, they cannot rely on visual information to perform the task. The task consists of 32 blocks of 8 trials. The inter-trial interval ranges from 2000 to 3000 ms. Before each block, participants are instructed to place their hands in one of four positions: both hands with palms facing up, both hands palms facing down, one hand palm up (left/right) and one hand palm down (right/left). With this manipulation, participants use of first person motor imagery can be checked through assessment of the posture effect: when using first person motor imagery, participants are faster for stimuli with a view that is congruent with the current posture of their own hand than for stimuli with a view that is incongruent with the posture of their hand (28). First person motor imagery use can further be corroborated by the effect of orientation: participants are faster for medially oriented stimuli that are associated with biomechanically easy movements towards the body midsagittal plane, than for laterally orientated stimuli, that are associated with biomechanically difficult movements away from the body midsagittal plane (28). Participants are to report whether the hand drawing on display presented a left or right hand by pressing the corresponding button with their left or right foot.
Behavioural performance on this task is evaluated by means of response times (i.e. time from stimulus onset to button press) and error rates (i.e. the number of incorrect trials divided by the total number of valid trials).
During the task, alertness is monitored with an eye monitor and bipolar surface electromyography (EMG) over both thumbs is performed, to monitor muscle activity indicative of hand movements and exclude the influence of overt movements.
3.3.3 Other parameters
Some measures will be collected to describe the study population and if applicable, to correct for possible confounding effects.
Demographic data that will be collected includes age, sex and education level.
b. NA characteristics
Several of the NA patients’ disease characteristics will be collected. These include disease onset and duration, history of prior attacks, and use of medication. Other characteristics may include, presence of atrophy, pattern of motor paresis, mechanical sensitivity of the plexus to pain, maximal severity of paresis during attack and duration of primary pain.
Relevant information on comorbid conditions and medication use will be collected.
d. Motor imagery ability
Individual differences in motor imagery ability exist (34). As a subject’s ability to imagine movements might affect his/her performance on the motor imagery tasks in this study, motor imagery ability is assessed with the short version of the Kinesthetic and visual imagery questionnaire (KVIQ-10). The KVIQ-10 assesses the clarity of the image (visual), and the intensity of the sensations (kinesthetic), that the subject is able to imagine from the first person perspective (35).
3.3.4 Exploratory outcomes
In addition to its primary and secondary outcomes, the NA-CONTROL study includes some exploratory outcome measures that have not been used before to study NA or any similar patient populations. They were added to the study to gain additional insight in the underlying mechanisms of the residual complaints in this disorder.
220.127.116.11 Cerebral (re)organisation
Central (re)organisation in NA will further be explored by means of additional MRI scans. For this purpose, functional and high-resolution anatomical images of the whole brain will be acquired on a 3T Siemens whole body scanner at the Donders Centre for Cognitive Neuroimaging. An eye monitor will be utilised during the MRI scanning to monitor alertness. In addition to the secondary MRI outcome (i.e. the HLJT motor imagery task-based functional MRI signal), two different neuroimaging markers of cerebral organisation will be used:
a. Functional (re)organisation in rest
Participants will be asked to lie still, think of nothing in particular and look at a fixation cross while 7 minutes of resting-state functional MRI data is obtained.
Changes in functional activity and connectivity of several brain areas and cognitive resting state networks (including the sensorimotor, fronto-parietal and executive control networks) will be analyzed primarily with independent component analysis techniques on resting state functional MRI data (36)
b. Structural (re)organisation
Cerebral grey and white matter changes will be assessed using structural brain analysis based on anatomical T1-weighted MRI scans. We will perform Voxel-Based Morphometry, a validated and fully automated technique for computational analysis of difference in global and local grey and/or white matter volume (37).
As this part of the study is exploratory, analyses of the resting-state functional MRI data and structural MRI data will not be focused on a priori regions or networks of interests. In addition to the resting-state functional MRI and structural MRI scans, a new first person motor imagery is employed to further assess motor planning and representations:
c. Neuromotor Encoding in Neuromuscular Scapular dyskinesia task (NENS-task)
This first person motor imagery task was specifically designed to investigate the impact of central motor planning in the clinical phenomenon of scapular dyskinesia. Participants are asked to imagine making pointing movements with their left or right elbow (novel movement) or finger (trained movements) towards targets shown on a computer screen, and to indicate with a right foot button press when they have finished imaging the movement (i.e. when they have reached the target with the specified body part). Performance is evaluated by means of response times. Response time is defined as the time from stimulus onset to button press.
For the NENS task, bipolar EMG of both serratus anterior muscles is used, to monitor muscle activity and exclude influence of overt movements. The NENS task is performed outside the MRI environment, seated behind a computer screen.
18.104.22.168 Other exploratory outcomes
a. Position and orientation of the scapula
The 3-dimensional (3D) position and orientation of the scapula will be explored with a new measurement protocol. Anatomical locations for marker placement will be identified through manual palpation by a trained assessor (author RL). These anatomical locations correspond to a thoracic reference plane (top and bottom of sternum, spine (C7, T8), and three bony landmarks of the scapula (the angulus inferior, trigonum spinae, angulus acromialis) (38) at three levels of anteflexion (0˚, 90˚ and 120˚). Marker locations will be captured with 3D-photography at the Radboudumc’s 3D-photography lab. Subsequent analyses will provide the position and orientation of the scapula relative to the thoracic reference coordinate system.
3.4 Randomisation and blinding
NA patients will be randomly assigned to either the experimental intervention to the usual care in a 1:1 ratio. Randomisation is done by a Good Clinical Practice (GCP) compliant system (Castor Electronic Data Capture), which employs stratified, variable block randomisation. To prevent uneven distribution of certain characteristics across groups, randomisation will be stratified according to two factors: sex (male/female), and age (4 blocks: 18-30, 30-42, 42-54, >54). Randomisation will be performed on site (at the Donders Institute for Brain Cognition and Behaviour, Centre for Cognitive Neuroimaging) after the participant has completed the baseline measurement (see Table 1).
Due to the project’s design, it is not possible to blind participants or the assessor. Participants will inevitably know whether they are receiving the rehabilitation program or usual care. The assessor cannot be blinded either for multiple reasons: all assessments are performed by a single assessor; as the number of assessments differs across groups, the assessor will know which participant belongs to which group; as the rehabilitation program takes place at the facility the assessor works at, the assessor could be de-blinded if she were to encounter a participant visiting the facility for treatment.
3.5 Withdrawal procedures
Participants can choose to withdraw their consent and leave the study at any time, without specifying the reason. No additional assessments will be obtained after a subject withdraws. Data that has been collected up until that point will be used for analyses. Participants have consented to this, as part of the original informed consent. Patients that want to withdraw from the study, can continue with the rehabilitation program outside the trial if they wish to do so.
The investigator or a member of the treatment team can decide to withdraw a subject from the study for urgent medical reasons. NA patients that have a recurrent attack during their participation will be withdrawn from the study.
If a patient is withdrawn from the study before their visit to the expert outpatient clinic, they are asked to come to the Rehabilitation or Neurology outpatient clinic for a single interdisciplinary visit to confirm their diagnosis of NA and provide treatment advise as usual.
3.6 Patient retention
Patient retention is promoted in several ways. When participating in the specific rehabilitation program, the patient is in regular contact with the Radboudumc treatment team (i.e. first 5 weekly visits, followed by 2 biweekly visits and 2 monthly visits over a 17 week period). Patients in the usual care group will be contacted at least 2 times during the 17 week control treatment period. The coordinating researcher will contact them by phone to inquire how the patient is doing and to remind them of the dairy in which they keep track of the care and/or treatment they have received. Both groups will be reminded about the post-treatment measurement(s) in the week prior to the upcoming visit.
The intervention under investigation is the rehabilitation program developed and offered at the Radboudumc. This experimental intervention is compared to the usual care for NA in the Netherlands.
3.7.1 Experimental intervention
The experimental intervention is a 17-week specific rehabilitation program. The program starts with a visit to the specialised outpatient ‘Plexus clinic’ in week 1. During this visit, the patient is examined by a multidisciplinary team consisting of a rehabilitation physician, neurologist, physical therapist and occupational therapist. This specialised multidisciplinary team analyses the problems of the patient and provides a diagnosis and treatment advice. This treatment advice is implemented through four weekly sessions in week 2–5, two biweekly sessions in week 6–9 and two monthly sessions in week 10–17 (see Figure 4 for an overview). Each of the 8 treatment sessions involves one hour of occupational therapy and one hour of physical therapy. When needed, interdisciplinary strategies are employed.
The model depicted in Figure 5 forms the basis for the rehabilitation program. This model consists of several components that are addressed during the intervention program. The program combines strategies of relearning motor control to normalise scapular stability and coordination (39), with strategies focused on self-management, including energy conservation (40), to enable daily occupations. The focus and extent to which components are addressed are adjusted to accommodate individual patients’ needs. For a full description of the rehabilitation program, see IJspeert, Janssen (14) and van Eijk, Groothuis (7).
3.7.2 Usual care (control group)
The 25 NA patients in the control group will receive usual care for 17 weeks. The usual care may vary for each individual, and may even consist of no treatment at all. Patients are asked to keep a diary during this period, in which they will report on the care/treatment they receive, including the type of care (e.g. physical or occupational therapy, acupuncture), number of sessions and composition of the care (e.g. strength training, aerobic training, massage). After 17 weeks, patients in the usual care group will start with the 17-week rehabilitation program at the Radboudumc as described above.
During the experimental intervention, co-interventions can be employed if needed. These co-interventions may include, but are not limited to, analgesics and steroid medication. While undergoing the experimental intervention, patients are asked to refrain from seeking additional treatment for the upper extremity outside the scope of the rehabilitation program (e.g. additional therapy or care), unless this is discussed with the treating physician in advance. The use of any co-interventions will be registered.
All participants are not allowed to participate in any other scientific study that might interfere with their participation in the NA-CONTROL study (from signing informed consent to completing the follow-up from home).
3.7.4 Post-trial care
If deemed necessary by the treating clinician and desired by the patient, the treatment can be extended after the 9 sessions that are part of the experimental intervention.
3.8 Data collection and management
3.8.1 Data collection
Data will be collected as described under outcomes. The assessor (the coordinating researcher) conducting the measurements is trained in collecting all measures that are obtained during the measurement protocol (i.e. operating MRI systems, applying bipolar EMG surface electrodes, conducting force measurements, palpating bony landmarks of the scapula and trunk, etc.).
3.8.2 Data management system
Most data is collected through lab based measurement systems, or entered directly in the electronic CRF in a GCP compliant electronic data management system (castor EDC, www.castoredc.com). This system utilises a log system with an automated audit trail. The Delegation of Responsibilities Log will identify all individuals responsible for data collection, handling and managing of the database.
A data management plan, detailing location of and access to study data and the code list, method of coding, back-up, locking, and archiving of data, code list and analysis files has been submitted to and approved by the Board of Directors of the Radboudumc.
3.9 Statistics and data analysis
3.9.1 Proposed analysis
For all continuous variables, summaries will be given, reporting number of (missing) observations, mean, standard deviation, median and range. For categorical variables, the summaries will report number of (missing) observations, and number and percentage in each category. This will be done for each time point (baseline, outcome measurement(s) and follow-up), and for the change from baseline for each intervention group separately.
The primary clinical outcome (SRQ-DLV score) and most other clinical outcomes are linear or quasi-linear. Generalised estimated equations analysis will be employed to investigate group differences in the intervention effects on primary and secondary outcome measures and to investigate the influence of possible effect modifiers. If necessary, analyses will be adjusted for group differences in functional capability of the upper extremity (SRQ-DLV score), age and sex at baseline. Data will be analyzed according to the intention to treat principle.
If necessary to satisfy modelling assumptions, appropriate transformations will be performed.
Prior to locking of the data, a statistical analysis plan will be drawn up and approved by a statistician and the principal investigator.
3.9.2 Missing data
Throughout data collection, measures will be taken, where possible, to minimise the occurrence of missing data. These measures include those mentioned under 3.6, Patient retention, as well as clear communication with individuals involved in data collection.
Once data collection is complete, the extent to which data is missing will be evaluated. Any patterns in missing data, especially in relation to the intervention groups, will be explored. If necessary and possible, missing data will be imputed.
3.10.1 Data monitoring
As this study has a negligible risk classification it does not require a data monitoring committee. The study will be monitored by an independent, certified monitor according to the Netherlands Federation of University Medical Centres’ guidelines for monitoring of clinical studies. The frequency and extent to which the study is monitored is defined in a monitor plan that has been submitted to and approved by the Board of Directors of the Radboudumc.
3.10.2 (Serious) Adverse events
All adverse events (AEs) reported spontaneously by the subject or observed by the investigator or the treatment team will be recorded. 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.
All serious adverse events (SAEs) will be reported to the accredited medical ethical committee following national regulations.
3.11 Good Clinical Practice
3.11.1 Ethical conduct of the study
The study will be conducted according to the principles of the Declaration of Helsinki (version 64th WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the Dutch Medical Research Involving Human Subjects Act (WMO).
All personnel involved in the conduction of this study has received training on GCP. The principles of GCP will be followed throughout the conduction of this study.
3.11.2 Protocol amendments
All amendments will be notified to the accredited medical ethical committee. Non-substantial amendments will not be notified but will be recorded and filed by the investigator. Substantial amendments will not be implemented until approval of the accredited medical ethical committee has been obtained. In case changes or additions to the protocol might influence participants’ decision to participate in the study, active participants will be informed and a new informed consent procedure will be started.
All clinical and research data collected for this study will be handled in such a way that participant confidentiality is ensured. All digital and hard copy records are kept in (digital) environments with limited access by appropriate staff only. Access rights and responsibilities are recorded on a designated list. Clinical information, images, and research data, will not be used by the study staff for any purposes other than the conduct of the study. Collection, sharing and maintenance of personal information during and after the study will comply with the international and national rules and regulations.
3.11.4 Study record retention
At the end of the study, all data will be checked and put into a validated database. Following Dutch national legislation, the database will be closed anonymously and stored in the sponsor’s archive for 15 years.
3.11.5 Insurance and indemnity
The sponsor has a liability insurance and a mandatory participants insurance for medical research involving human participants which is in accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory lnsurance for Clinical Research in Humans of 2015).
3.12 Reporting publications, and notification of results
3.12.1 Scientific publications
Anonymised results will be published in national and international peer-reviewed journals.
3.12.2 Communication and dissemination
As the (inter)national expertise centre for NA, the Radboudumc plays a key role in forming treatment guidelines and education of (peripheral) rehabilitation centres and primary care. This position enables rapid transfer of newly emerging knowledge on disease mechanisms and treatment obtained through this trial to the medical community. New treatment modalities, or adjusted or improved rehabilitation programs can therefore be implemented rapidly.
Lay-friendly outcomes will be communicated to participants through trial newsletters and with the broader patient population through patient organisations. Where appropriate, information will be disseminated through newsletters, websites and at conferences in collaboration with patient organisations.
3.12.3 Authorship policy
Data arising from this study will be owned by the trial team and their employer. Authorship of publications coming from this study will follow the research code: publications are submitted only with authors who have made a substantial contribution to the research.
3.12.4 Peer review
The original proposal for the NA-CONTROL study has been reviewed by external reviewers appointed by the Prinses Beatrix Spierfonds, as part of the funding review process.