Principal Investigator: Lee  Dibble
Keywords: Parkinson disease , treadmill training , disease modulation , high intensity exercise , walking Department: Physical Therapy/Athletic Training
IRB Number: 00136463
Specialty: Neurology, Physical Therapy, Radiology, Neurology, Neurology, Neurology, Radiology
Sub Specialties: Neuroimaging, Nuclear Medicine, Neuropathology, Movement Disorders, Parkinson's Disease, Neuroradiology
Recruitment Status: Recruiting

Contact Information

Genevieve Olivier

Brief Summary

This study is a Phase 3 multi-site, randomized, evaluator-masked, study of endurance treadmill exercise on changes in the MDS-UPDRS Part III score at 12 months. 370 participants will be randomly assigned to 2 groups: 1)60-65% HRmax or 2)80-85% HRmax 4 times per week. Secondary objectives will test hypotheses related to striatal specific binding ratio (SSBR) at 12 months, MDS-UPDRS Part III score, ambulatory mobility (6-minute walk), daily walking activity (steps), cognition, quality of life, cardiorespiratory fitness, blood-derived biomarkers of inflammation and neurotrophic factors at 12 and 18 months. Exploratory objectives will test hypotheses related to the effects of removing the study support that was provided over 18 months on the sustainability and durability of the exercise effects at 24 months.

Primary Objective(s): To test whether the progression of the signs of PD is attenuated at 12 months in non-medicated people with PD when they perform high-intensity endurance treadmill exercise.

Secondary Objectives: To test in non-medicated people with PD, 1) whether there is a reduction in the percent decline of the quantified DaTscan™ SPECT (SSBR) at 12 months, 2) whether the progression of the signs of PD (MDS-UPDRS III) is attenuated at 18 months when they continue to perform high-intensity endurance treadmill exercise, and 3) the effects of high-intensity endurance exercise on  ambulatory mobility, daily walking activity, cognition, quality of life, cognition, time to initiate dopaminergic therapy and dose of dopaminergic medication, blood-derived biomarkers of inflammation, and neurotrophic factors at 12 and 18 months.

Exploratory Objectives: To test whether the progression of the signs of PD is also attenuated at 24 months in non-medicated people with PD when they continue to exercise for an additional 6 months under their own supervision.

Inclusion Criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1.         A diagnosis of idiopathic PD based on the modified *UK PD brain bank criteria. 38-40 and which are consistent with recent criteria proposed for clinically established early established Parkinson's disease that no longer exclude individuals with a family history of Parkinson's disease.41

•          The UK Parkinson’s disease Society Brain Bank clinical diagnostic criteria are a three-step process as listed below.  We are listing all criterion but will not be using those related to levodopa.

•          Step 1 Diagnosis of Parkinsonian Syndrome

o          Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions)

o          And at least one of the following:

          Muscular rigidity

          4-6 Hz rest tremor

          Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction

•          Step 2 Exclusion Criteria for Parkinson’s Disease

o          History of repeated strokes with stepwise progression of parkinsonian features

o          History of repeated head injury

o          History of definite encephalitis

o          Oculogyric crises

o          Neuroleptic treatment at onset of symptoms

o          Sustained remission

o          Strictly unilateral features after three years

o          Supranuclear gaze palsy

o          Cerebellar signs

o          Early severe autonomic involvement

o          Early severe dementia with disturbances of memory, language and praxis

o          Babinski sign

o          Presence of cerebral tumor or communicating hydrocephalus on CT scan

o          Negative response to large doses of levodopa (if malabsorption excluded)

o          MPTP exposure

(*modified criteria are being applied in this study, to allow PD diagnosis in individuals with more than one relative affected by PD)

•          Step 3 Supportive prospective positive criteria for Parkinson’s disease (Three or more required of definite Parkinson’s disease)

o          Unilateral onset

o          Rest tremor present

o          Progressive disorder

2.         Hoehn and Yahr stage less than 3

3.         Disease duration: less than 3 years since disease diagnosis

4.         Age 40-80 years

5.         Positive DaTscan™ SPECT by qualitative visual assessment from the Institute of Neurodegenerative Disorders.

i.          For women: If not surgically sterile or postmenopausal, a negative pregnancy test will be required prior to receiving the DaTscan™ SPECT.

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1.         Currently being treated with PD medications such as levodopa or dopamine receptor agonists, MAO-B inhibitors, amantadine, or anticholinergics.

2.         Expected to require treatment with medication for PD in the first 6 months of the study.

3.         Use of any PD medication 60 days prior to the baseline visit including but not limited to levodopa, direct dopamine agonists, amantadine, Rasagiline (Azilect), Selegiline (Eldepryl), Artane (trihexyphenidyl), Mucuna.

4.         Duration of previous use of medications for PD exceeds 30 days.

5.         Use of neuroleptics/dopamine receptor blockers for more than 30 days in the year prior to baseline visit, or any use within 30 days of baseline visit

6.         Presence of known cardiovascular, metabolic, or renal disease or individuals with major signs or symptoms suggestive of cardiovascular, metabolic, or renal disease without medical clearance to participate in the exercise program.

7.         Uncontrolled hypertension (resting blood pressure >150/90 mmHg) 

8.         Individuals with orthostatic hypotension and standing systolic BP below 100 will be excluded. Orthostatic hypotension (OH) is a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.

9.         Hypo- or hyperthyroidism (TSH <0.5 or >5.0 mU/L), abnormal liver function (AST or ALT more than 2 times the upper limit of normal), abnormal renal function (creatinine clearance calculated by the Cockcroft-Gault equation <50mL/min, or estimated glomerular filtration rate using the MDRD4 equation or the CKD-EPI equation <45mL/min/1.73m2 ).

10.       Complete Blood Count (CBC) out of range and physician’s judgment that abnormal value is clinically significant.

11.       Recent use of psychotropic medications (e.g., anxiolytics, hypnotics, benzodiazepines, antidepressants) where dosage has not been stable for 28 days prior to screening.

12.       Serious illness (requiring systemic treatment and/or hospitalization) within the last 4 weeks. 

13.       Any other clinically significant medical condition, psychiatric condition, drug or alcohol abuse, assessment or laboratory abnormality that would, in the judgment of the investigator, interfere with the subject's ability to participate in the study.

14.       Montreal Cognitive Assessment (MoCA) score of <26 to rule out mild cognitive impairment (MCI).

15.       Beck Depression Inventory II (BDI) score > 16, indicating depression that precludes ability to exercise. Any subject with such a score will be referred to a PCP or physician for further evaluation and management of depression.

16.       Individuals participating in 120 minutes or more of moderate intensity exercise per week within the last 6 months will be excluded. Moderate intensity is defined as a range greater than 60-65% HRmax. These individuals are excluded since their exercise activities are equal to or greater than the activities they would experience if they were assigned to the 60-65% treatment group.

17.       Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: bupropion, modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, any amphetamine or amphetamine derivative. These can compromise DaTscan™ SPECT.

18.       Known allergy to iodinated products.

19.       Known hypersensitivity to DaTscan™ SPECT (either to the active substance of 123I-ioflupane or any of the excipients.

20.       Prior SPECT scan within 6 months of baseline scan. Recruitment will be delayed for individuals who have had a previous SPECT scan within 6 months of the baseline scan. If the SPECT scan was performed for the PPMI2.0 study within the 8 weeks prior to the projected SPARX3 baseline visit, the PPMI2.0 SPECT scan will be used for SPARX3 and the participant will not be excluded.

21.       (For women only) Pregnant, or plan to become pregnant in the next 12 months.

22.       Other disorders, injuries, diseases, or conditions that might interfere with ability to perform endurance exercises (e.g. history of stroke, respiratory problems, traumatic brain injury, orthopedic injury, or neuromuscular disease).