Measuring Parkinson's Disease Progression (MPDP)

Dopamine Buffering Capacity Measured by phMRI as a Novel Biomarker of Disease Progression in PD

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Drug: Levodopa

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).

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine, Movement Disorders Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 79 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: PD Group; A broad range of Parkinson's disease severity and disease duration. Some subjects will not be treated currently with levodopa, and thus likely will be early in the disease process.

Drug: Levodopa; At least 1 hour after 200mg carbidopa p.o., each subject will receive an intravenous solution of levodopa in saline at a rate based on age and body mass according to the "final dose" described in Black et al 2003.The total dose for a 70-year-old, 70kg subject will be approximately 65mg. Subjects with untreated PD will then take 6 ± 1 weeks of clinically dosed oral carbidopa-levodopa tablets for clinical purposes and then repeat the carbidopa plus intravenous levodopa dose as above.; Other Names: Carbidopa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ke measured by phMRI	Effect site rate constant measured by serum levodopa concentrations and regional cerebral blood flow. Note, there are no outcome measures relevant to clinical care. This is not a placebo-controlled treatment study.	2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effect ratings	Nausea/vomiting, sleepiness, dizziness or lightheadedness, and overall feeling poorly or well, are each measured on a horizontal visual analog scale before and at the end of the i.v. levodopa infusion	2 hours

Collaborators and Investigators

• Sponsor: Kevin J. Black, MD
• Collaborators: The Michael J. Fox Foundation for Parkinson's Research

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 19, 2017
• Primary Completion (ACTUAL): October 18, 2019
• Study Completion (ACTUAL): October 19, 2019

Study Registration Dates

• First Submitted: June 29, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (ACTUAL): July 2, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 14, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: levodopa; Parkinson's disease; PD
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Disease Progression; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Levodopa; Carbidopa
• Other Study ID Numbers: 009 (Other Identifier: Nahrain Medical Research Collective (NMRC))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will publicly share a fully anonymized set of linked data from this study. No protected health information (PHI) will be shared.
• IPD Sharing Time Frame: 36 months after completion of last participant
• IPD Sharing Access Criteria: Public
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No