Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02598973 |
| Other study ID # |
N2012-W |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2016 |
| Est. completion date |
January 31, 2022 |
Study information
| Verified date |
April 2021 |
| Source |
VA Office of Research and Development |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Parkinson's disease (PD) is a common neurodegenerative disorder affecting approximately
80,000 Veterans, representing a priority area for VA research. Current medicines for PD only
improve symptoms, treatments that slow disease progression are needed, and earlier diagnosis
of PD may be the key to their development. PD symptoms can be mimicked by medicines (most
commonly antipsychotic drugs that block dopamine), and some of these patients actually have
underlying "prodromal" PD that was "unmasked" years before it would have caused symptoms.
This problem is increasing as these medicines are now used for common conditions including
post-traumatic stress disorder and depression. The investigators will identify prodromal PD
in patients with drug-induced symptoms using brain scans. These patients will be enrolled in
a randomized clinical trial of aerobic exercise which slows progression in animal models of
PD and has other health benefits. The investigators will measure the effect of exercise on
symptoms, disease progression (using brain scans) and markers of PD risk (using blood tests).
These studies will improve early PD diagnosis and potentially identify a way to slow
progression of PD.
Description:
Parkinson's disease (PD) is an incurable neurodegenerative disorder affecting approximately 1
million US adults and about 80,000 Veterans. PD causes significant morbidity due to motor and
non-motor symptoms across its prolonged course with an annual economic burden of $14 billion
in the US alone. Motor symptoms associated with loss of dopaminergic neurons in PD may be
temporarily improved with dopamine replacing medicines, but disease-modifying therapies that
delay or prevent neuronal loss are lacking and sorely needed. Exercise is promising as a
disease-modifying therapy because it protects dopaminergic neurons in animal models of PD and
has been associated with measures of neuroplasticity in PD patients. Unfortunately, more than
half of dopaminergic neurons in the substantia nigra are lost before motor symptoms occur
making it difficult to identify patients early enough to benefit from potentially
disease-modifying therapies. Early "prodromal" PD can be identified using non-motor features
including olfactory dysfunction and other biomarkers such as dopamine transporter (DaT) brain
imaging abnormalities that are apparent years before motor symptoms. However, these
strategies would be difficult and costly to implement on a population level without first
identifying high-risk individuals for screening. Commonly prescribed dopamine blocking
antipsychotic drugs cause debilitating PD-like motor dysfunction that is difficult to treat,
and in some patients this finding may serve as a "stress test" for failing dopaminergic
networks unmasking symptoms long before they would normally appear. Identifying prodromal PD
among drug-induced parkinsonism patients offers a unique and unexplored opportunity for early
intervention.
In the proposed studies, the investigators will employ a tiered screening strategy with
inexpensive and non-invasive olfactory testing in drug-induced parkinsonism patients followed
by DaT imaging in individuals with olfactory impairment to identify a cohort of patients with
presumed prodromal PD. Subjects with presumed prodromal PD will then be randomized to a
home-based exercise intervention ({5} times weekly aerobic walking confirmed by remote
activity monitors) or no intervention. In this cohort, the investigators will assess: 1)
Short-term symptomatic effects of exercise on motor function in drug-induced parkinsonism
using standard clinical measures (Unified Parkinson's Disease Rating Scale) and quantitative
gait assessments after 8 weeks of intervention; 2) a potential disease-modifying effect after
52 weeks of exercise by comparing the rate of change in quantitative DaT imaging; and 3) the
mechanisms and biochemical correlates of exercise-induced changes using a panel of serum
biomarkers implicated in exercise and/or PD risk including brain-derived neurotrophic factor,
uric acid, and apolipoproteinA1. Differences in the rate of change between groups will be
assessed using independent samples t-tests and linear mixed-effects models adjusting for age
and gender. The investigators' preliminary data demonstrates a strong association between
olfactory impairment and abnormal DaT imaging in drug-induced parkinsonism. Based on power
calculations allowing for 20% dropout, the investigators will screen approximately 250
drug-induced parkinsonism subjects using olfactory testing, with the expectation that
approximately 88 will have abnormal DaT imaging and agree to participate in the intervention
trial.
Antipsychotic drugs are widely prescribed for a growing list of approved indications and
off-label uses including bipolar disorder, depression and post-traumatic stress disorder.
Studying drug-induced parkinsonism patients with prodromal PD will allow us to identify which
individuals are at risk, characterize the natural history of progression and evaluate
appropriate management strategies at the earliest stages of PD. Exercise as a putative
disease-modifying therapy offers significant advantages including cost, ease of access and
lack of toxicity compared with unproven pharmacologic interventions especially if offered
early enough to have meaningful clinical impact.
