Basal Ganglia Diseases, Brain Diseases, Central Nervous System Diseases, Cerebral Disorder, Nervous System Diseases, Neurodegenerative Diseases, Parkinson Disease, Parkinsonian Disorders, Prodromal Stage, REM Sleep Behavior Disorder, Synucleinopathies
Conditions
Keywords
Physical Activity, Prevention, Remote, Mobile Health (mHealth), Feasibility, Exercise, Digital biomarker, Blood, Imaging, MRI, Motivational application, Walking, Parkinson Disease, Prodromal
Brief summary
The goal of this clinical trial is to investigate the feasibility if a remotely administered smartphone app can increase the volume and intensity of physical activity in daily life in patients with isolated Rapid Eye Movement (REM) sleep behaviour disorder over a long period of time (24 months). Participants will be tasked to achieve an incremental increase of daily steps (volume) and amount of minutes exercised at a certain heart rate (intensity) with respect to their own baseline level. Motivation with regards to physical activity will entirely be communicated through the study specific Slow Speed smartphone app. Primary outcomes will be compliance expressed as longitudinal change in digital measures of physical activity (step count) measured using a Fitbit smartwatch. Exploratory outcomes entail retention rate, completeness of remote digital biomarker assessments, digital prodromal motor and non-motor features of PD, blood biomarkers and brain imaging markers. Using these biomarkers, we aim to develop a composite score (prodromal load score) to estimate the total prodromal load. An international exercise study with fellow researchers in the United States and United Kingdom are currently in preparation (Slow-SPEED). Our intention is to analyse overlapping outcomes combined where possible through a meta-analysis plan, to obtain insight on (determinants of) heterogeneity in compliance and possible efficacy across subgroups
Detailed description
Rationale: Parkinson's Disease (PD) is the fastest growing neurodegenerative disease. Exercise beneficially effects motor symptoms and neuroplasticity in people with PD. However, disease-slowing interventions have been ineffective in clinically manifest PD, when pathology is already advanced, but could succeed in prodromal PD, when pathology is limited. People with an isolated Rapid Eye Movement (REM) sleep Behaviour Disorder (iRBD) have a high risk to develop clinically manifest PD or a related neurodegenerative disease and are therefore considered to have probable prodromal PD. This study will take an important step forward by studying the feasibility and preliminary efficacy of long-term physical activity on prodromal symptoms and disease progression in people with probable prodromal PD using a newly developed, fully remote smartphone-based app. The app is inspired by the app used in the STEPWISE trial (NCT04848077). Objective: The goal of this clinical trial is to investigate whether a smartphone app can increase the volume and intensity of physical activity in daily life in patients with iRBD at risk of developing PD for a long period of time (24 months). The secondary aim is the potential group effect on physical fitness, digital prodromal motor- and non-motor symptoms. Thirdly, we investigate whether the intervention, prodromal motor- and non-motor symptoms can be assessed remotely in a digital, decentralized fashion. Fourthly, we aim to investigate the effect on imaging- and fluid biomarkers to identify markers for prodromal progression. Using these biomarkers, we aim to develop a composite score (prodromal load score) to estimate the total prodromal load. The anticipated fluid biomarkers outcomes are subject to potential alterations in the event of the development and implementation of novel techniques and/or biomarkers during the course of this study. Study design: Double-blind randomized controlled trial Study population: A total of 110 Dutch patients with iRBD (ICSD-3 criteria) aged 50 years and older, who are in possession of a suitable smartphone without mobility hampering conditions and absence of cognitive impairment which impedes usage of a smartphone will be recruited Intervention: Participants will be randomized to a group and will be motivated to increase the volume and intensity of physical activity based on their own baseline level. The groups differ in the amount of physical activity that they are tasked to achieve.
Interventions
A motivational smartphone application will be available for all participants using their own smartphone: the Slow-SPEED app. The Slow-SPEED app will motivate participants to increase the volume and intensity of their physical activity in daily life over a long period of time (2 years) based on their own baseline levels. Different treatment arms will receive different physical activity goals. The app offers participants feedback and support, that will stimulate them to reach their individual physical activity goal (i.e. incremental relative increase of step count and minutes exerting ≥ 64% of maximum heart rate reflecting MVPA relative to baseline level.).
Sponsors
McGill University
University of Pittsburgh
Radboud University Medical Center
Stichting ParkinsonNL
ZonMw: The Netherlands Organisation for Health Research and Development
Michael J. Fox Foundation for Parkinson's Research
Parkinson's UK
Cure Parkinson's
Edmond J. Safra Foundation
Davis Phinney Foundation
Donders Centre for Cognitive Neuroimaging
Anne Wojcicki Foundation
Sleep Medicine Centre Kempenhaeghe
Sleep Medicine Centre SEIN
Queen Mary University of London
23andMe, Inc.
Parkinsons Progression Markers Initiative (PPMI)
Massachusetts General Hospital
Harvard School of Public Health (HSPH)
IJsfontein B.V., Netherlands
Hoffmann-La Roche
Erasmus Medical Center
University of Illinois at Chicago
University of Rochester
University of Bristol
University of Plymouth
University of Luebeck
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Double-blind randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* previously diagnosed with iRBD meeting the following criteria according to the International Classification of Sleep Disorders (ICSD-3) * able to understand the Dutch language * being able to walk independently inside the home without the use of a walking aid * Not in a high physical activity range during the 4-week eligibility and baseline period * in possession of a suitable smartphone compatible with the Slow-SPEED app, the Fitbit app and the Roche PD Research Mobile application.
Exclusion criteria
* clinically diagnosed or self-reported diagnosis neurodegenerative disease; * self-reported weekly falls in the previous 3 months; * dexterity problems or cognitive impairments hampering smartphone use; * if they do not wish to be informed about an increased risk of developing diseases associated with iRBD * if individual is not community-dwelling
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean change in step count per day | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Mean change in step count per day as measured continuously with a smartwatch. Mean steps per day will be calculated from 4-week periods. Higher positive change in step count indicate more volume of physical activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in self-reported sleep quality (PSQI) | Week 0 (baseline), week 52 (1 year), week 104 (follow-up) | Change from baseline (week 0) on the Pittsburgh Sleep Quality Index (PSQI) at week 52 (1 year) and week 104 (follow-up). Range 0-21. Higher scores indicate worse sleep quality. |
| Change in olfaction (UPSIT) | Week 0 (baseline), week 104 (follow-up) | Change from baseline (week 0) on the University of Pennsylvania Smell Identification Test (UPSIT) at week 104 (follow-up). Range 0-40. Higher scores indicate better function. |
| Change in motor symptoms (Roche PD Research mobile application) | Week 0 (baseline), week 6, week 12, week 18, week 24, week 30, week 36, week 42, week 48, week 54, week 60, week 66, week 72, week 78, week 84, week 90, week 96, week 102 | Change in motor symptoms measured digitally with the smartphone using the Roche PD Research mobile application. Higher scores indicate worse function. |
| Change in metabolism (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on glucose and HbA1c at follow-up (week 104). Optional at week 26, week 52 and week 78. Lower scores indicate better metabolism. |
| Number of completed questionnaires on group level (completeness of digital assessments) | Week 0 (baseline), week 52, week 104 (follow-up) | Number of completed questionnaires |
| Number of smartwatch data points on group level (completeness of digital assessments) | Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up) | Number of data points received for each selected smartwatch parameter |
| Total smartwatch wear time on group level (completeness of digital assessments) | Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up) | Total smartwatch wear time |
| Number of Roche PD Research mobile application data points on group level (completeness of digital assessments) | Week 0 (baseline), week 6, week 12, week 18, week 24, week 30, week 36, week 42, week 48, week 54, week 60, week 66, week 72, week 78, week 84, week 90, week 96, week 102 | Number of data points received |
| Number of interactions with Slow-SPEED app on a group level | Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up) | Total times opening the app |
| Change in moderate to vigorous physical activity (MVPA) per day | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Change in number of minutes exerting (minimally) ≥ 64% of maximum heart rate, reflecting moderate intense physical activity, measured continuously using a smartwatch. Mean minutes per day will be calculated from 4-week periods. Higher positive change in minutes of MVPA indicate more aerobic physical activity. |
| Change in resting heart rate (physical fitness) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Change in resting heart rate per day as measured continuously with a smartwatch. Mean resting heart rate per day will be calculated from 4-week periods. Higher negative change (i.e. lower resting heart rate) indicate better function. |
| Change in heart rate variability (physical fitness) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Change in heart rate variability in Root Mean Square of Successive Differences (RMSSD) measured every 5 minutes with a smartwatch. Mean RMSSD per day will be calculated from 4-week periods. Higher positive change in RMSSD indicate better function. |
| Change in blood pressure (physical fitness) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) blood pressure in mmHg assessed by a sphygmomanometer at follow-up (week 104). Lower scores indicate better function. |
| Change in VO2max (physical fitness) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Change in VO2max in ml/kg/min measured per day with a smartwatch. Mean VO2max per day will be calculated from 4-week periods. Higher positive change in VO2max indicate better function. |
| Change in heart rate variability (autonomic function) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Mean change in heart rate variability in Root Mean Square of Successive Differences (RMSSD) measured every 5 minutes with a smartwatch. Mean RMSSD per day will be calculated from 4-week periods. Higher positive change in RMSSD indicate better function. |
| Change in orthostatic blood pressure (autonomic function) | Week 0 (baseline) and week 104 (follow-up) | Change in baseline (week 0) difference between supine and standing blood pressure measured with a sphygmomanometer to follow-up (week 104). Higher change indicate more autonomic dysfunction. |
| Change in anxiety and depression (HADS) | Week 0 (baseline), week 52 (1 year), week 104 (follow-up) | Change from baseline (week 0) on the Hospital Anxiety and Depression Scale (HADS) at week 52 (1 year) and week 104 (follow-up). Range 0-42. Higher scores indicate worse function. |
| Change in cognition (MoCA) | Week 0 (baseline), week 104 (follow-up) | Change from baseline (week 0) on the Montreal Cognitive Assessment (MoCA) at week 104 (follow-up). Range 0-30. Higher scores indicate better function. |
| Mean change in light sleep (sleep stage) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Mean change in light sleep stage measured continuously with a smartwatch. Mean duration of light sleep per day will be calculated from 4-week periods. Higher positive change indicate more light sleep. |
| Mean change in deep sleep (sleep stage) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Mean change in deep sleep stage measured continuously with a smartwatch. Mean duration of deep sleep per day will be calculated from 4-week periods. Higher positive change indicate more deep sleep. |
| Change in inflammation (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on Tumor Necrosis Factor-α, Interleukin-6 (IL-6), IL-18, IGF-1, clusterin, Il-10, PGC-α (irisin) at follow-up (week 104). Optional at week 26, week 52 and week 78. Lower inflammatory markers indicate less inflammation. Higher anti-inflammatory markers indicate less inflammation. |
| Change in growth factors (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on brain-derived neurotrophic factor (BDNF), Glial cell line-derived neurotrophic factor (GDNF), Platelet-derived growth factor (PDGF), Growth/differentiation factor 15 (GDF15) and Epidermal growth factor (EGF) at follow-up (week 104). Optional at week 26, week 52 and week 78. Higher growth factors indicate better function. |
| Change in ageing mechanism (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on klotho at follow-up (week 104). Optional at week 26, week 52 and week 78. High ageing marker indicate better function (i.e. less aging) |
| Change in pathological protein (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on α-synuclein at follow-up (week 104). Optional at week 26, week 52 and week 78. Low pathological protein indicate better function (i.e. less pathological process). |
| Change in neurodegeneration (blood based biomarkers) | Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up) | Change from baseline (week 0) on Neurofilament light (NfL) at follow-up (week 104). Optional at week 26, week 52 and week 78. Lower neurodegeneration markers indicate less neurodegeneration. |
| Change in brain volume (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on T1 Voxel-Based-Morphometry (VBM) at follow-up (week 104). Higher scores indicate higher volume. |
| Change in white matter hyperintensities (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on FLAIR at follow-up (week 104). Higher scores indicate worse status. |
| Change in basal ganglia; cortex [1] (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on resting-state functional MRI (Rs-fMRI) at follow-up (week 104). Higher scores indicate better functional connectivity. |
| Change in basal ganglia; cortex [2] (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on task-based functional MRI at follow-up (week 104). Higher scores indicate better functional connectivity. |
| Change in substantia nigra [1] (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on diffusion tensor imaging (DTI) at follow-up (week 104). Higher scores indicate better tissue integrity. |
| Change in substantia nigra [2] (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on Quantitative Susceptibility Mapping (QSM) at follow-up (week 104). Higher scores indicate more iron loading. |
| Change in substantia nigra [3]; locus coeruleus (imaging biomarkers) | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on neuromelanin at follow-up (week 104). Higher scores indicate better tissue integrity. |
| Change in instrumental activities of daily living (ADL) (functional status) | Week 0 (baseline), week 52 (1 year) and week 104 (follow-up) | Change from baseline (week 0) on Lawton instrumental ADL (iADL) scale at week 52 (1 year) and 104 (follow-up). Range 0-14. Higher score indicate better function. |
| Change in WHOQoL-BREF (quality of life) | Week 0 (baseline), week 52 (1 year) and week 104 (follow-up) | Change from baseline (week 0) on World Health Organization Quality of Life Questionnaire - BREF (WHOQoL-BREF) scale at week 52 (1 year) and 104 (follow-up). Range 0-100. Higher score indicate better quality of life. |
| Change in Research and Development (RAND-36)/Short Form health survey (SF-36) (quality of life) | Week 0 (baseline), week 52 (1 year) and week 104 (follow-up) | Change from baseline (week 0) on RAND-36/SF-36 scale at week 52 (1 year) and 104 (follow-up). Range 0-100. Higher score indicate better quality of life. |
| System Usability (SUS) | week 104 (follow-up) | Usability of the Slow-SPEED-NL application assessed by the Dutch version of the System Usability Scale (SUS) at week 52 (year 1) and week 104 (follow-up). Range 0-100. Higher score indicate better usability. |
| Barriers and motivators to engage in physical activity | Week 0 (baseline) and week 104 (follow-up) | Barriers and motivators to engage in physical activity reported on a self-developed questionnaire |
| Change in phenoconversion neurodegenerative disease | Week 0 (baseline) and week 104 (follow-up) | Change from baseline (week 0) on phenoconversion in Parkinson's Disease (PD), Lewy body dementia (LBD) and multiple system atrophy (MSA). Higher scores indicate more phenoconversion. |
| Change in step count on a group level (compliance) | Week -4 until 0 (baseline) compared to week 0-26, week 26-52, week 52-78, week 78-104 | Change from week -4 until 0 (baseline period) mean step count per day compared to mean step count in 6 month periods. Mean step count per day will be calculated from 4-week periods. Scored as number of participants able to increase step count per day 0-25%, 26-50%, 51-75%, 76-100% relative to their own baseline measure |
| Change in moderate to vigorous physical activity per day on a group level (compliance) | Week -4 until 0 (baseline) compared to week 0-26, week 26-52, week 52-78, week 78-104 | Change from week -4 until 0 (baseline period) number of minutes exerting (minimally) ≥ 64% of maximum heart rate in 6 month periods. Mean minutes per day will be calculated from 4-week periods. Scored as number of participants to increase 0-25%, 26-50%, 51-75%, 76-100% relative to their own baseline measure |
| Number of completed step week goals on a group level (compliance) | Week 0 (baseline) and week 104 (follow-up) | Total number of completed step count week goals |
| Number of completed aerobic activity (MVPA intensity) week goals on a group level (compliance) | Week 0 (baseline) and week 104 (follow-up) | Total number of completed aerobic activity (MVPA intensity) week goals |
| Mean change in REM sleep (sleep stage) | All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period) | Mean change in rapid eye movement (REM) sleep stage measured continuously with a smartwatch. Mean duration of REM sleep per day will be calculated from 4-week periods. Higher positive change indicate more REM sleep. |
| Number of drop-outs on a group level (retention rate) | Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up) | Number of drop-outs throughout the study |
Countries
Netherlands
Contacts
CONTACTThomas Oosterhof, MSc
PRINCIPAL_INVESTIGATORSirwan KL Darweesh, PhD
Radboudumc Department of Neurology
Outcome results
None listed