Clinical trial NCT03205956: Measuring Parkinson's Disease Progression
Official title: Dopamine Buffering Capacity Measured by phMRI as a Novel Biomarker of Disease Progression in PD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Parkinson's Disease
Keywords: Parkinson's disease
PD
levodopa
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: The Michael J. Fox Foundation for Parkinson's Research
First posted: 2017-07-02
Enrollment: 31
Sex: ALL
Minimum age (years): 40
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants receive oral carbidopa before, and i.v. levodopa during brain imaging, to measure regional cerebral blood flow responses to levodopa.
Primary purpose: OTHER

Brief summary: The Measuring Parkinson's Disease Progression study aims to use MRI scans and a controlled dose of levodopa to find a biomarker (objective measurement) of Parkinson's disease (PD). Biomarkers would help determine the effectiveness of therapies in slowing or stopping PD progression, and accelerate the pace of research.

Detailed description: Early in the course of Parkinson's disease, a small dose of levodopa (L-DOPA) provides benefit for many hours. The body responds as if the levodopa in the plasma filled a reservoir and then slowly leaked out to produce benefit. With disease progression, even though the same amount of levodopa circulates in the blood, the benefit wears off much faster, as if the reservoir had become leakier. This wearing off of benefit can be characterized by a single number, the effect site rate constant Ke. On average, patients with more severe disease and longer disease duration have a larger ("leakier") Ke when the response to drug is measured using clinical features like tapping speed. Unfortunately, clinical measurements are influenced by confounding factors such as patient fatigue and comfort. A direct, objective brain measure of response to levodopa may improve the reliability of this measurement. Fortunately, we can assess the effect of levodopa on the brain directly, using an MRI machine to measure blood flow in different parts of the brain. For instance, the midbrain has a robust blood flow response to a single, clinically sensible dose of levodopa. This study's goal is to validate MRI measurement of Ke in the brain as an objective, quantitative measure of disease severity in PD. We will do this by comparing MRI-based Ke values from people with PD across a wide range of disease duration and severity. In a subgroup of participants, we will do this measurement twice, once before treatment and once after 6 weeks of treatment with carbidopa-levodopa (Sinemet® and other brand names).

Eligibility criteria: Inclusion Criteria:

* Age 40-79 at screening
* Meet accepted diagnostic criteria for Parkinson disease

Exclusion Criteria: Key exclusion criteria:

* Deep brain stimulator (DBS)
* Pregnancy
* Patients taking a dopamine antagonist (like quetiapine) or dopamine partial agonist (like aripiprazole)
* Metal in the head or eye, or other contraindication to MRI
* Claustrophobia
* Serious neurologic disease other than PD
* Head trauma with loss of consciousness for more than 5 minutes
* Severe or unstable systemic illness
* Certain psychiatric illnesses (dementia, psychosis, current major depression)
* Current alcohol use disorder
* Subjects who feel that going without nicotine for 3-4 hours would be uncomfortable
* Currently taking an extended-release formulation of a dopamine agonist (like Mirapex ER or Requip XL)

Primary outcomes:
measure: Ke measured by phMRI
timeFrame: 2 hours
Secondary outcomes:
measure: Side effect ratings
timeFrame: 2 hours
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Movement Disorders Center
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Kevin J Black, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Black KJ, Carl JL, Hartlein JM, Warren SL, Hershey T, Perlmutter JS. Rapid intravenous loading of levodopa for human research: clinical results. J Neurosci Methods. 2003 Jul 15;127(1):19-29. doi: 10.1016/s0165-0270(03)00096-7.
citation: Siddiqi SH, Abraham NK, Geiger CL, Karimi M, Perlmutter JS, Black KJ. The Human Experience with Intravenous Levodopa. Front Pharmacol. 2016 Jan 6;6:307. doi: 10.3389/fphar.2015.00307. eCollection 2015.
citation: Koller JM, Vachon MJ, Bretthorst GL, Black KJ. Rapid Quantitative Pharmacodynamic Imaging with Bayesian Estimation. Front Neurosci. 2016 Apr 8;10:144. doi: 10.3389/fnins.2016.00144. eCollection 2016.
citation: Black KJ, Acevedo HK, Koller JM. Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease. Front Neurol. 2020 May 6;11:370. doi: 10.3389/fneur.2020.00370. eCollection 2020.