Clinical trial NCT03808675: Aerobic Exercise in Parkinson's Disease
Official title: Long Term Aerobic Exercise to Slow Progression in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Parkinson's Disease
Keywords: Parkinson's disease
Exercise
Aerobic exercise
Cognition
Driving
Diffusion tensor imaging
DTI
MRI
Depression
Cardiorespiratory Fitness
Quality of life
Health education
Executive functions
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Iowa
First posted: 2019-01-17
Enrollment: 57
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: One-year, single-blind, parallel group, randomized controlled trial (RCT) that compares the effects of moderate aerobic exercise vs. usual care + health education
Primary purpose: TREATMENT

Brief summary: Parkinson's disease (PD) is an incurable brain illness that afflicts more than one million Americans, including many aging Veterans. PD places an unbearable burden on the individual due to progressive impairment of movement and mental function. As a result, patients lose critical abilities such as driving and can become isolated. Although drugs and surgery help movement problems, their benefits are temporary and may cause side effects. Drugs provide limited and temporary benefit for cognition and do not prevent dementia. Animal and preliminary human studies on aerobic exercise show promising results in helping a broad spectrum of symptoms. However, due to limited and inconsistent research results, the long term effects of aerobic exercise on brain health and clinical features in PD is unknown. The investigators will conduct a clinical trial to test the long term effects of aerobic exercise on the brain tissue, movement, mental functions, and driving in PD. If effective, aerobic exercise can be implemented immediately as a low cost, easily accessible treatment in PD.

Detailed description: Parkinson's disease (PD) culminates in dementia, immobility, and death at a huge societal cost. Even early in the course, motor and cognitive dysfunction impairs instrumental activities of daily living (IADL). Non-motor symptoms due to fatigue, mood, sleep, and autonomic disorders further reduce quality of life (QoL). DTI shows progressive decline in brain tissue integrity. Usual care of PD centers on medical and surgical treatments relieve motor symptoms, but these cause side effects and lose efficacy over time. Usual treatment for non motor manifestations with pharmaceuticals (e.g., antidepressants) is symptomatic and not specific for PD. Acetylcholine esterase inhibitors exert modest symptomatic benefits on dementia, but there is no approved treatment for mild cognitive impairment. Physical Therapy is usually prescribed in later stages when mobility impairment ensues. There is no approved standard exercise regimen for PD. There is no cure or disease modifying treatment. Thus, there is a critical need for treatments that provide broad spectrum of benefits and slow PD.

Preliminary research suggests that aerobic exercise has potential to meet this need. However, aerobic exercise is demanding and carries some risks. It is unknown if aerobic exercise is more beneficial than usual care in PD in long term due to gaps in the investigators knowledge about the effects of cardiorespiratory fitness (CRF) on brain tissue integrity, motor function, cognition, IADL, QoL, and disease progression. Limitations of current studies include short duration, small sample size, lack or inadequacy of controls, lack of outcome measures for cognition and IADL, and lack of biological markers to measure progression. The objective in this application is to fill the translational gap by determining the biological, clinical, and functional effects of long term aerobic exercise (LTAE) in PD.

The overall hypothesis is that LTAE improves brain tissue integrity and slows down PD. The FIRST AIM is to determine the effects of LTAE on clinical features and functional abilities in PD. The investigators' prior 6-month, uncontrolled trial showed preliminary evidence that aerobic exercise improves aspects of motor function, cognition, and QoL in PD, but long term outcomes and implication for functional abilities are unknown. The investigators hypothesize that LTAE will provide sustained improvement in motor function, cognition, and non-motor symptoms with translation of benefits to QoL and IADL. The investigators will test this with a one-year randomized controlled trial (RCT) that compares the effects of moderate aerobic exercise vs usual care. The investigators will use driving as the outcome for IADL. Driving represents an important symbol for independence, and depends on integrity of cognitive and motor systems. The SECOND AIM is to determine the mechanism of LTAE effects in PD. CRF reflects complex improvements in vascular, cardiac, and metabolic health from aerobic exercise. There is preliminary evidence that higher CRF is associated with better brain health and motor/cognitive function, and that aerobic exercise improves these outcomes. For example, the investigators' preliminary study showed improvement of microtissue integrity in the striatum and white matter on DTI, but it is unclear how these changes counteract PD progression over long term. The hypotheses are: 1) LTAE will improve brain tissue integrity as indexed by DTI, 2) LTAE effects on motor and cognitive function are mediated by changes in brain tissue integrity on DTI, and 3) physiological processes leading to improved CRF from AE are critical to the benefits on the brain tissue integrity and motor/cognitive function. The investigators will test these hypotheses determining the effects of LTAE on CRF and DTI, and the association between individual differences in training related changes in motor and cognitive function, DTI, and CRF.

In summary, the investigators' proposal leverages the diverse interdisciplinary team, strong preliminary data and past work, and unique infrastructure to determine if LTAE slows down neurodegeneration and clinical disability in PD.

Eligibility criteria: Inclusion Criteria:

* Men or women aged 40 and older with the diagnosis of idiopathic PD per UK Brain Bank criteria
* Hoehn-Yahr Stage I-III, on stable dopaminergic treatment regimen for equal or greater than 4 weeks prior to baseline.
* Aerobic Fitness: VO2max below "very good" fitness levels for their age and gender at baseline cyle ergometry.

To include subjects who have room to improve their aerobic fitness, the investigators will enroll only those subjects whose VO2max is below "very good" fitness level (about 90% of the population) using age and gender based VO2max norms based review of 62 studies where VO2max was measured directly in healthy adult subjects in the USA, Canada and 7 European countries (Reference: Shvartz, E and Reibold, RC. Aerobic fitness norms for males and females aged 6 to 75 years: a review.

Aviat Space Environ Med. 1990; 61:3-11).

* Cognitive function: No dementia per Movement Disorder Society Level I criteria (Reference: Dubois, B, Burn, D, Goetz, C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007; 22:2314-2324).
* Current active drivers with a valid driver's license
* Veteran or non-veteran

Exclusion Criteria:

* Subjects unwilling or unable to give informed consent
* Secondary parkinsonism (e.g., drug induced)
* Parkinson-plus syndromes
* History of brain surgery for PD such as deep brain stimulation
* Corrected visual acuity less than 20/50 (due to effect on driving)
* Contraindications to exercise per ACSM criteria for Exercise Testing and Training (Reference: American College of Sports Medicine. Cardiorespiratory Exercise Prescription. In: Ehrman JK, ed. ACSM's Guidelines for Exercise Testing and Prescription.6th ed. Baltimore: Lippincott Williams \& Wilkins, 2010:448-462).
* No confounding acute or unstable medical, psychiatric, orthopedic condition. Subjects who have hypertension, diabetes mellitus, depression, or other common age related illness will be included if their disease under control with stable treatment regimen for at least 30 days.
* Clinically significant TBI or PTSD
* Presence of other known medical or psychiatric comorbidity that in the investigator's opinion would compromise participation in the study
* Presence of dementia per Movement Disorder Society Level I criteria
* Subjects with clinically significant depression as determined by a Beck Depression Inventory (BDI) score greater than 15 at the screening visit
* History of exposure to typical or atypical antipsychotics or other dopamine blocking agents within 6 months prior to the baseline visit
* Use of investigational drugs within 30 days before screening
* Subjects have to be on a stable regimen of central nervous system acting medications (benzodiazepines, antidepressants, hypnotics) for 30 days prior to the baseline visit
* Contraindication to having a brain MRI

Primary outcomes:
measure: OFF period MDS-UPDRS Motor Subscale score
timeFrame: Change from Baseline OFF period MDS-UPDRS Motor Subscale score at 1 year
measure: Percent Increase Score (PIS) on Eriksen's flanker task
timeFrame: Change from Baseline Percent Increase Score (PIS) on Eriksen's flanker task at 1 year
measure: total number of driving safety errors on road test
timeFrame: Change from Baseline total number of driving safety errors on road test at 1 year
measure: regional DTI (diffusion tensor imaging)
timeFrame: Change from Baseline regional DTI at 1 year
measure: MDS-UPDRS Non-motor Experiences of Daily Living subscale (Part I) score
timeFrame: Change from Baseline MDS-UPDRS Non-motor Experiences of Daily Living subscale (Part I) score at 1 year
measure: Summary index of the Parkinson's Disease Questionnaire-39 (PDQ-39)
timeFrame: Change from Baseline PDQ-39 Summary Index at 1 year
Secondary outcomes:
measure: ON Period MDS-UPDRS motor examination subscale score
timeFrame: Change from Baseline ON Period MDS-UPDRS motor examination subscale score at 1 year
measure: Dexterity (time on 9-hole peg board) test of NIH Toolbox motor battery
timeFrame: Change from Baseline 9-hole peg board test performance at 1 year
measure: COGSTAT score
timeFrame: Change from Baseline COGSTAT score at 1 year
measure: Radial Diffusivity (rD) on Diffusion imaging tractography
timeFrame: Change from Baseline Diffusion imaging tractography at 1 year
measure: Geriatric Depression Scale (GDS) score
timeFrame: Change from Baseline GDS score at 1 year
measure: Motor experiences of daily living score
timeFrame: Change from Baseline motor experiences of daily living score at 1 year
measure: Beck Anxiety Inventory (BAI) score
timeFrame: Change from Baseline BAI score at 1 year
measure: Parkinson's Disease Sleep Scale version 2 (PDSS-2)
timeFrame: Change from Baseline PDSS-2 score at 1 year
measure: Fatigue Severity Scale (FSS)
timeFrame: Change from Baseline FSS score at 1 year
measure: Locomotion (time on 25-f walk test for gait speed) test
timeFrame: Change from Baseline Locomotion (time on 25-f walk test for gait speed) test performance at 1 year
measure: Locomotion (time on 4-m walk test for gait speed) test of NIH Toolbox motor battery
timeFrame: Change from Baseline Locomotion (time on 4-m walk test for gait speed) test performance at 1 year
measure: Finger Tapping test
timeFrame: Change from Baseline average performance for right and left finger tapping at 1 year
measure: Endurance (distance on 6-minute walk) test
timeFrame: Change from Baseline Endurance (distance on 6-minute walk) test performance at 1 year
measure: Schwab and England Activities of Daily Living Scale
timeFrame: Change from Baseline score at 1 year
measure: Mini-Mental Status Examination (MMSE)
timeFrame: Change from Baseline MMSE score at 1 year
measure: Montreal Cognitive Assessment (MOCA)
timeFrame: Change from Baseline MOCA score at 1 year
measure: Pelli-Robson Contrast Sensitivity
timeFrame: Change from Baseline score at 1 year
measure: Early Treatment Diabetic Retinopathy Study (ETDRS)
timeFrame: Change from Baseline score at 1 year
measure: EEG
timeFrame: Change from Baseline metrics at 1 year
Other outcomes:
measure: VO2max on cycle ergometry
timeFrame: Change from Baseline VO2max on cycle ergometry at 1 year
Locations:
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Iowa City
country: United States
facility: Iowa City VA Health Care System, Iowa City, IA
state: Iowa
Study officials:
affiliation: Iowa City VA Health Care System, Iowa City, IA
name: Ergun Y. Uc, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Uc EY, Doerschug KC, Magnotta V, Dawson JD, Thomsen TR, Kline JN, Rizzo M, Newman SR, Mehta S, Grabowski TJ, Bruss J, Blanchette DR, Anderson SW, Voss MW, Kramer AF, Darling WG. Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Neurology. 2014 Jul 29;83(5):413-25. doi: 10.1212/WNL.0000000000000644. Epub 2014 Jul 2.