Pragmatic Cyclical Lower Extremity Exercise Trial for Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: The Cleveland Clinic

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Title: Pragmatic Cyclical Lower Extremity Exercise Trial for Parkinson’s disease 
 
NCT #: NCT04000360 
 
Document Date: November 9, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title: Pragmatic Cyclical Lower Extremity Exercise for Parkinson’s Trial 
PI: Jay L. Alberts 
Date Modified: 11/9/2021 
 
SPECIFIC AIMS 
An unmet need in the treatment of Parkinson’s Disease (PD) is identification of an effective disease-modifying 
intervention (e.g. pharmaceutical, surgical or behavioral).1,2 Increasing evidence, from our laboratory3-7 and 
others,8-10 coupled with our recently completed NIH-sponsored randomized controlled trial (RCT), CYClical 
Lower Extremity exercise for Parkinson’s trial (CYCLE), indicates high intensity aerobic exercise is a candidate 
to alter PD progression.  CYCLE trial data demonstrate that exercise delivered in a controlled, supervised 
laboratory setting results in global improvements in motor and non-motor function.  Global improvements were 
preserved following exercise cessation, suggesting exercise is likely enhancing CNS function.3,4,7 The precise 
mechanism underlying improved post-exercise motor function in PD is unknown. Our imaging data5,6,11 and 
others12,13 suggest a plausible mechanism is improved thalamo-cortical connectivity, facilitated through 
elevation of neurotrophic factors.14,15 A multi-site pragmatic RCT is proposed, in which PD patients complete 
the CYCLE protocol at home, to address the following questions: 1) What are the disease-altering capabilities 
of a PD-specific long-term, high intensity aerobic exercise intervention?  2) What are the relationships of 
patients’ phenotype and exercise performance variables to PD progression within such an exercise program? 
Based on preliminary data, we hypothesize that long-term high-intensity aerobic exercise slows PD 
progression relative to Usual and Customary Care (UCC).  In sum, approximately 250 mild to moderate PD 
patients from Cleveland Clinic and University of Utah will be randomized to a high-intensity home exercise or a 
UCC group. The CYCLE protocol, involving aerobic intensity between 60-80% of heart rate reserve with a 
target cadence between 80-90 RPMs, will be delivered to the patients’ home via the commercially available 
Peloton Cycle. The exercise group will be asked to cycle 3x/week for 12 months.  The UCC group will be 
instructed to engage in their normal activities. The Movement Disorder Society Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS III) will be used to evaluate disease progression or rate of physical decline.  
Blinded MDS-UPDRS III evaluations will be completed at: enrollment, 6 and 12 months.  Biomechanical iPad 
assessments of motor and non-motor function16-19 will be completed at each time point; thus augmenting 
clinical outcomes to provide a comprehensive understanding of the effects extended exercise on specific 
aspects of PD motor control and executive function. Overall activity levels will be monitored for both groups via 
a wearable sensor.  
Aim 1: To determine the disease-altering effects of a home-based high-intensity aerobic exercise 
program.  12-month MDS-UPDRS III rate of decline while off medication will serve as the primary outcome. 
Hypothesis: Those in the high intensity exercise group will have a significantly smaller one-year rate of decline 
in MDS-UPDRS III scores compared to the UCC group.  
Aim 2: To determine the effects of a home-based aerobic exercise program on upper and lower 
extremity function using biomechanical outcomes. Our Nine Hole Peg Test (9HPT),19 gait speed19 and 
Timed Up and Go (iTUG)20,21 iPad modules will be used to quantify upper and lower extremity function. 
Hypothesis: Performance on 9HPT, gait speed and iTUG will show significantly slower rates of decay over 12 
months for those in the exercise group compared to the UCC group. 
Aim 3: To determine the effects of a home-based aerobic exercise program on non-motor function. 
Non-motor assessments will be evaluated using our iPad-based tests of processing speed (Processing Speed 
Test19,22), working memory and set switching (Trail Making Test A & B). 
Hypothesis: Rates of decline in executive functions from enrollment to 12 months will be significantly less in the 
exercise group compared to the UCC group. 
Aim 4: To develop a prognostic model to predict 12-month MDS-UPDRS III decline for patients 
participating in a home-based high-intensity aerobic exercise program.  
PD demographics (age, gender, disease duration, primary symptoms, age of onset, etc.) coupled with exercise 
performance variables (compliance, duration, cadence, heart rate, power, heart rate variability) will be used to 
predict 12-month change in MDS-UPDRS III scores among the exercise cohort. 
Hypothesis:  Demographics, baseline PD status and comorbidities, and exercise performance will predict 12-
month PD progression.  Time in target heart rate zone and cadence, particularly, will notably improve 
predictions over those from baseline measures only. 
 

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APPROACH                                                                             
To test the hypothesis that high intensity exercise completed 
by PD patients in their the home can alter disease 
progression, we will consent and randomize approximately 
250 CC and UU PD patients to home-based high-intensity 
aerobic exercise or UCC within 3 years, and monitor group 
exercise parameters, activity levels, and PD progression in 
both groups.  The trial will be conducted under Data Safety 
Monitoring Board (DSMB) oversight.   
Participant Recruitment, Screening and Randomization: 
CC’s Center for Neurological Restoration (CNR) manages 
6,000+ PD patients; each patient typically has semi-annual 
neurology visits which include a complete MDS-UPDRS III 
evaluation. UU’s Movement Disorders Program manages 
2,000+ PD patients.  Their respective Directors, Drs. 
Fernandez (Cleveland) and Moretti (Utah), will lead their 
medical teams to screen in recruiting for this project and will 
complete MDS-UPDRS III clinical evaluations, blinded to 
group assignment. The pragmatic clinical trial design, with 
exercise at home and relatively few visits to the study site, 
will minimize travel burden, easing recruitment and 
facilitating recruitment of a racially and socio-economically 
diverse patient group.23 It is anticipated that study sites will 
enroll an equal number of participants. Adults with idiopathic 
PD who meet inclusion criteria and cleared for exercise will 
be randomized to either the home exercise or UCC group, using a permuted block randomization stratified by 
site, with random block sizes of 8, 10, or 12 for the first 8 blocks at each site, and 4, 6, or 8 subsequently, 
preloaded into a secure and shared RedCap electronic data management system developed at CC. Both sites 
have effectively utilized RedCap across in previous multi-site clinical trials,24-31 and clinical programs. Figure 1 
depicts study flow.  Total study participation time is projected to be 12.5 months, including ~2.5 weeks for cycle 
delivery and completion of initial Comprehensive Assessments (On-/Off- meds).  
As shown in Figure 1, three Comprehensive assessments of motor and non-motor function will be conducted 
for all participants. Comprehensive (90 mins) assessments (Table 1) will be overseen by Drs. Fernandez and 
Moretti, and will be completed at project enrollment (On- and Off-medication), 6 months (Off-medication), and 
12 months (Off-medication). Visit windows will be within ± 10 days of their nominal dates. Participants will be 
reimbursed for time and travel expenses of $50 for each assessment. All clinical and self-report data will be 
entered into the RedCap database (see Data and Safety Monitoring). Each site’s biomechanical data from the 
iPad will be uploaded securely, with encryption, to the CC HIPAA-compliant cloud instance (ClearData), 
processed in the cloud, and integrated into the Alberts lab’s on-premises, firewall protected, server. 
Asking participants to withhold medication for Off-state examinations imposes a burden, but the Off-
state (12 hours off meds) will increase insight into the direct effect of exercise on PD itself. Since medication 
changes are frequent with PD and often result in symptomatic fluctuations, the Off-state provides a more 
reliable, less confounded time comparisons.  Medication reconciliation will be completed at each examination,  
and levodopa equivalent daily doses (LEDDs) will be determined and utilized in the prediction model (Aim 4).  
To determine the potential impact of overall physical activity in disease progression, all patients will be 
provided a Garmin activity monitor to measure overall daily activity (e.g., active minutes and steps per day). 
Currently, the Garmin activity monitor is utilized by 30,000+ participants in the CC Health System employee 
health plan, and accurately counts steps and activity levels of individuals with PD.32 Patients will wear the 
device on their belt/waistband or shoe during waking hours and upload the data every 30 days via the supplied 
application.  Device batteries typically last ~6-months.  To ensure no loss of data the battery will be replaced at 
the 6 month assessment.  Activity monitor data will be synchronized with the secure CC Health system portal 
and downloaded to the Alberts research server behind the CC firewall.  The number of steps and minutes of 
activity, binned by day, week, month and year, will be considered for inclusion in the predictive model in Aim 4.  

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Leveraging a Widespread Consumer-based Home Exercise Platform:  Our previous model of deploying a 
consumer-based interactive and connected exercise cycle to the home will be leveraged for this trial.27 The 
Peloton Indoor Cycle (New York, NY) will serve as the platform to deliver the CYCLE exercise protocol and 
actively measure exercise performance variables.  To ensure safety in exercising and understanding of the 
Peloton, exercise participants will be properly fit to the Peloton. Dr. Alberts and Dr. Dibble will be responsible 
for conducting this fitting session as both have extensive experience in fitting PD patients on exercise cycles.  
During this session seat height, reach, clipless or platform pedals, etc. will be optimized for comfort and safety 
in mounting and dismounting the cycle.  Patients will complete a tutorial related to using the cycle, heart rate 
monitor and data transmission.  Patients will be informed of their target HRR (Karvonen method: [(220-age)-
resting HR] x 60-80% + resting HR) and complete a brief exercise session to ensure they fully understand the 
exercise requirements and Peloton interface.  They will be provided a Garmin activity monitoring device and 
instructed on its use.  Within 10 days of the clinical fitting session, a Peloton cycle will be delivered to the 
patient’s home by a certified technician.  They will assemble and setup the cycle according to patient-specific 
fitting specifications. The certified technician will ensure all aspects of the cycle are working properly.  The 
study coordinator will contact the patient within 48 hours of delivery to ensure the system is functioning as 
intended.  
Standardized High-Intensity Home Exercise Program: The Peloton platform contains thousands of pre-
recorded cycling classes with varying levels of intensities and recommendations. Study staff will select cycling 
protocols from this pre-recorded list for cyclists entering the study at different levels of fitness (beginners, 
intermediate, or advanced). Participants will be safely increased in RPMs, heart rate, and overall levels of 
perceived exertion over subsequent weeks of the study to reach study recommendations. Participants will be 
will be asked to exercise on the Peloton 3 times per week for 50-60 minutes (40 minutes at their target HRR + 
5-10 minute warm-up and cool-down) for 12 months and encouraged to exercise using a relatively high 
cadence (80-90 rpms).  To increase engagement, modules containing different professional Peloton instructors 
will be utilized.  All instances of the modules will be similar in terms of aerobic intensity; however they will vary 
in type of background music and general personality of the instructor.  In addition to the selected CYCLE 
modules, the patient will have the option to join more than 20 daily “live” sessions or select one of 300+ scenic 
courses on the Peloton platform.  These additional options empower each patient to exercise in a manner best 
suited for them and will facilitate compliance.  Considering the Peloton records, stores, and transmits heart 
rate, power, speed, estimated distance, time and cadence for every exercise session, regardless of whether 
the patient is completing a CYCLE module, live class or scenic ride, the specific module they complete is not 
critical as data are recorded, transmitted and downloaded to the study database regardless. Secure data 
transmission procedures are detailed in Protection of Human Subjects. 
Study staff at each site will make bi-monthly calls to patients to address technology issues or compliance 
obstacles for those patients not meeting exercise recommendations.  During these calls, exercise may be 
Outcome Measure 
Domain 
Comprehensive 
Aim 1 
 
 
MDS-UPDRS III  
Rater-observed PD global motor symptoms 
✔ 
Aim 2 
 
 
Nine Hole Peg Test  
Upper extremity dexterity 
✔ 
Timed Up & Go & 10M walk 
Transfers, turning, gait speed 
✔ 
Postural sway 
Postural stability and Balance 
✔ 
Self-reported falls 
Prospectively recorded via fall diary 
✔ 
Six Minute Walk Test   
Cardiovascular fitness 
✔ 
Aim 3 
 
 
Processing Speed  
Info processing speed, implicit learning 
✔ 
Visual Memory Test 
Episodic Memory 
✔ 
Trail Making Test A & B  
Set-switching, attention, working memory  
✔ 
Neuro-QoL 
Quality of life questionnaire 
✔ 
MDS-UPDRS I, II, IV 
Part I: non-motor symptoms; Part II: self-reported motor 
symptoms; Part IV: motor complications 
✔ 

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progressed as deemed appropriate based on physiological signs monitored by the Peloton and patient 
subjective report (see Protection of Human Subjects for details).  
Usual and Customary Care Group: Participants randomized to the UCC group will be asked to maintain their 
current exercise habits for 12 months. UCC can entail referrals to physical or occupational therapy or voluntary 
exercise. Due to the overwhelming evidence that those services are beneficial to individuals with PD, we will 
not restrict individuals from those programs. Similar to the home exercise group, a member of the study team 
will call these patients twice per month to inquire about activity levels, medication changes and technology 
assistance with the activity monitoring device and data.   
 
Alternate Data Capture: 
Due to the Covid-19 situation, the Cleveland Clinic and the University of Utah are requesting the ability to 
conduct virtual visits with participants. The Cleveland Clinic will utilize either FaceTime or Zoom, and the 
University of Utah will utilize the preferred platforms of their institution.  
 
 
Inclusion/Exclusion Criteria: 
Inclusion Criteria: 
a) Adult with a diagnosis of idiopathic PD by a physician or physician extender 
b) Hoehn and Yahr stage I-III 
c) Demonstrate the ability to safely mount and dismount the Peloton stationary cycle  
d) In-home WiFi (Peloton system requires WiFi to transmit exercise data)* 
*2017 report indicates WiFi rates of 76% and 83% in Ohio and Utah households respectively 
Exclusion Criteria:  
a) Participation in pharmaceutical or behavioral disease modifying PD-related clinical trial or study 
b) Diagnosis of dementia or any neurocognitive impairment that compromises one’s ability to provide 
informed consent. 
c) Implanted deep brain stimulation electrodes 
d) Recommendation for medical clearance using the American College of Sports Medicine (ACSM) 
Preparticipation Health Screen (Figure 2)33 
a. If the ACSM screen recommends medical clearance, the subject must obtain medical clearance 
by their health care provider prior to participation.  
b. Those who choose not to obtain physician clearance will not be eligible for participation. Those 
who do not receive physician clearance for high intensity exercise will not be eligible.  
e) A musculoskeletal issue (arthritis, osteoporosis, back problem) that would limit one’s ability to engage 
in exercise 
f) Neurological disease other than Parkinson’s disease (i.e. multiple sclerosis, Huntington’s disease) 
g) Current or active cardiac arrhythmia 
h) DeNovo patients (have not begun Parkinson’s disease medications). 
i) Previous or planned treatment of focused ultrasound for Parkinson’s disease management 
 
  

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