Slow-SPEED-NL: Slowing Parkinson's Early Through Exercise Dosage-Netherlands (Slow-SPEED-NL)

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

Study Overview

• Status: Recruiting
• Conditions: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinson Disease; Parkinsonian Disorders; Basal Ganglia Diseases; Synucleinopathies; Neurodegenerative Diseases; REM Sleep Behavior Disorder; Prodromal Stage; Cerebral Disorder
• Intervention / Treatment: Behavioral: Increase of physical activity volume and intensity with the use of a motivational smartphone application

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.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas Oosterhof, MSc; Phone Number: 0031631647857; Email: thomas.oosterhof@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Recruiting
      • Radboud University Medical Center
      • Contact: Thomas Oosterhof, MSc; Phone Number: +31631647857; Email: slow-speed@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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
• equal to or less than 120 minutes of sports/outdoor activities per day (question 5-28 LASA Physical Activity Questionnaire (LAPAQ))
• less than an average 7,000 steps/day 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 Mobile application v2.

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

Exclusion criteria for MRI only:

• history of epilepsy, structural brain abnormalities (i.e. stroke, traumatic defects, large arachnoid cysts) or brain surgery
• claustrophobia
• implanted electrical devices (i.e. pacemaker, deep-brain stimulator (DBS), neurostimulator)
• metal implants (such as prosthetics, ossicle prosthesis, metal plates or other non-removable metal part) or metal splinters
• pregnancy
• fear for incidental finding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Large proportional increase in step count and minutes exerting moderate to vigorous physical activity (MVPA) relative to baseline level.	Behavioral: Increase of physical activity volume and intensity with the use of a motivational smartphone application; 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.).
Active Comparator: Active control; Small proportional increase in step count and minute exerting moderate to vigorous physical activity (MVPA) relative to baseline level.	Behavioral: Increase of physical activity volume and intensity with the use of a motivational smartphone application; 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.).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in step count per day	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.	All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of physical activity prior to study (LAPAQ)	Question 5-28 Longitudinal Aging Study Amsterdam Physical Activity Questionnaire (LAPAQ). Every question is scored from 0-5, which respectively correspond to 0, 1-15, 16-30, 31-60, 61-120 en >120 minutes per day. Higher LAPAQ indicate more activity.	Week -4
Change in moderate to vigorous physical activity (MVPA) per day	Change in amount 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.	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 (physical fitness)	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.	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 (physical fitness)	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.	All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period)
Change in blood pressure (physical fitness)	Change from baseline (week 0) blood pressure in mmHg assessed by a sphygmomanometer at follow-up (week 104). Lower scores indicate better function.	Week 0 (baseline) and week 104 (follow-up)
Change in VO2max (physical fitness)	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.	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 (autonomic function)	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.	All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period)
Change in orthostatic blood pressure (autonomic function)	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.	Week 0 (baseline) and week 104 (follow-up)
Change in anxiety and depression (HADS)	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.	Week 0 (baseline), week 52 (1 year), week 104 (follow-up)
Change in cognition (MoCA)	Change from baseline (week 0) on the Montreal Cognitive Assessment (MoCA) at week 104 (follow-up). Range 0-30. Higher scores indicate better function.	Week 0 (baseline), week 104 (follow-up)
Mean change in light sleep (sleep stage)	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.	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 (sleep stage)	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.	All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period)
Mean change in REM sleep (sleep stage)	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.	All 4 week periods between and including week -4 until 0 (baseline period) and week 100 until 104 (follow-up period)
Change in self-reported sleep quality (PSQI)	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.	Week 0 (baseline), week 52 (1 year), week 104 (follow-up)
Change in olfaction (UPSIT)	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.	Week 0 (baseline), week 104 (follow-up)
Change in motor symptoms (Roche PD mobile application v2)	Change in motor symptoms measured digitally with the smartphone using the Roche mobile PD application v2. Higher scores indicate worse function.	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 metabolism (blood based biomarkers)	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.	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)
Change in inflammation (blood based biomarkers)	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.	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)
Change in brain volume (imaging biomarkers)	Change from baseline (week 0) on T1 Voxel-Based-Morphometry (VBM) at follow-up (week 104). Higher scores indicate higher volume.	Week 0 (baseline) and week 104 (follow-up)
Change in white matter hyperintensities (imaging biomarkers)	Change from baseline (week 0) on FLAIR at follow-up (week 104). Higher scores indicate worse status.	Week 0 (baseline) and week 104 (follow-up)
Change in basal ganglia; cortex [1] (imaging biomarkers)	Change from baseline (week 0) on resting-state functional MRI (Rs-fMRI) at follow-up (week 104). Higher scores indicate better functional connectivity.	Week 0 (baseline) and week 104 (follow-up)
Change in basal ganglia; cortex [2] (imaging biomarkers)	Change from baseline (week 0) on task-based functional MRI at follow-up (week 104). Higher scores indicate better functional connectivity.	Week 0 (baseline) and week 104 (follow-up)
Change in substantia nigra [1] (imaging biomarkers)	Change from baseline (week 0) on diffusion tensor imaging (DTI) at follow-up (week 104). Higher scores indicate better tissue integrity.	Week 0 (baseline) and week 104 (follow-up)
Change in substantia nigra [2] (imaging biomarkers)	Change from baseline (week 0) on Quantitative Susceptibility Mapping (QSM) at follow-up (week 104). Higher scores indicate more iron loading.	Week 0 (baseline) and week 104 (follow-up)
Change in substantia nigra [3]; locus coeruleus (imaging biomarkers)	Change from baseline (week 0) on neuromelanin at follow-up (week 104). Higher scores indicate better tissue integrity.	Week 0 (baseline) and week 104 (follow-up)
Change in instrumental activities of daily living (ADL) (functional status)	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.	Week 0 (baseline), week 52 (1 year) and week 104 (follow-up)
Change in WHOQoL-BREF (quality of life)	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.	Week 0 (baseline), week 52 (1 year) and week 104 (follow-up)
Change in Research and Development (RAND-36)/Short Form health survey (SF-36) (quality of life)	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.	Week 0 (baseline), week 52 (1 year) and week 104 (follow-up)
System Usability (SUS)	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.	week 104 (follow-up)
Barriers and motivators to engage in physical activity	Barriers and motivators to engage in physical activity reported on a self-developed questionnaire	Week 0 (baseline) and week 104 (follow-up)
Change in phenoconversion neurodegenerative disease	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.	Week 0 (baseline) and week 104 (follow-up)
Change in step count on a group level (compliance)	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 amount of participants able to increase step count per day 0-25%, 26-50%, 51-75%, 76-100% relative to their own baseline measure	Week -4 until 0 (baseline) compared to week 0-26, week 26-52, week 52-78, week 78-104
Change in moderate to vigorous physical activity per day on a group level (compliance)	Change from week -4 until 0 (baseline period) amount 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 amount of participants to increase 0-25%, 26-50%, 51-75%, 76-100% relative to their own baseline measure	Week -4 until 0 (baseline) compared to week 0-26, week 26-52, week 52-78, week 78-104
Amount of completed step week goals on a group level (compliance)	Total amount of completed step count week goals	Week 0 (baseline) and week 104 (follow-up)
Amount of completed aerobic activity week goals on a group level (compliance)	Total amount of completed aerobic activity week goals	Week 0 (baseline) and week 104 (follow-up)
Amount of drop-outs on a group level (retention rate)	Amount of drop-outs throughout the study	Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up)
Amount of interaction with Slow-SPEED app on a group level	Total times opening the app	Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up)
Amount of completed questionnaires on group level (completeness of digital assessments)	Amount of completed questionnaires	Week 0 (baseline), week 52, week 104 (follow-up)
Amount of smartwatch data points on group level (completeness of digital assessments)	Amount of data points received for each selected smartwatch parameter	Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up)
Total smartwatch wear time on group level (completeness of digital assessments)	Total smartwatch wear time	Week 0 (baseline), week 26, week 52, week 78, week 104 (follow-up)
Amount of Roche PD mobile application v2 data points on group level (completeness of digital assessments)	Amount of data points received	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 growth factors (blood based biomarkers)	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.	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)
Change in ageing mechanism (blood based biomarkers)	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)	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)
Change in pathological protein (blood based biomarkers)	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).	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)
Change in neurodegeneration (blood based biomarkers)	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.	Week 0 (baseline), week 26 (optional), week 52 (optional), week 78 (optional) and week 104 (follow-up)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Massachusetts General Hospital; McGill University; Hoffmann-La Roche; University of Pittsburgh; University of Illinois at Chicago; Erasmus Medical Center; Queen Mary University of London; University of Bristol; University of Luebeck; University of Rochester; University of Plymouth; Michael J. Fox Foundation for Parkinson's Research; Harvard School of Public Health (HSPH); ZonMw: The Netherlands Organisation for Health Research and Development; 23andMe, Inc.; Sleep Medicine Centre Kempenhaeghe; Davis Phinney Foundation; PARKINSONS UK; Stichting ParkinsonNL; Cure Parkinsons; Edmond J. Safra Foundation; Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen; Anne Wojcicki Foundation; Sleep Medicine Centre SEIN; Parkinsons Progression Markers Initiative (PPMI); IJsfontein B.V., Netherlands
• Investigators: Principal Investigator: Sirwan KL Darweesh, PhD, Radboudumc department of Neurology

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 21, 2023
• First Submitted That Met QC Criteria: December 21, 2023
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Physical Activity; Exercise; Imaging; Feasibility; Prevention; Parkinson Disease; Walking; Blood; Prodromal; Remote; Motivational application; Mobile Health (mHealth); Digital biomarker
• Additional Relevant MeSH Terms: Metabolic Diseases; Sleep Wake Disorders; Movement Disorders; Parasomnias; Proteostasis Deficiencies; REM Sleep Parasomnias; Parkinson Disease; Mental Disorders; Nervous System Diseases; Brain Diseases; Neurodegenerative Diseases; Parkinsonian Disorders; Synucleinopathies; Prodromal Symptoms; REM Sleep Behavior Disorder; Central Nervous System Diseases; Basal Ganglia Diseases
• Other Study ID Numbers: NL84072.091.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will make relevant anonymised data available in a database.
• IPD Sharing Time Frame: We will make relevant anonymised data available in a database after publication of the main results of our trial.
• IPD Sharing Access Criteria: Researchers who are interested in re-use of the data are asked to contact the central contact person for permission.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No