Parkinson DiseasePhase 4NCT04821830
Vigor and the LDR in Parkinson Disease
A Phase 4 study testing carbidopa/levodopa, as prescribed by treating physician in people with Parkinson Disease, run by University of Michigan at 1 site in United States.
Trial summary
Parkinson disease (PD) is a common disorder in which reduced speed of movement results from inadequate brain production of the chemical dopamine. The most effective treatment for PD is the drug levo-dopa, which partially replaces brain dopamine. Read more about this study
- Who is it for?
- Ages 45 to 90 years
- Conditions the study is for
- Parkinson Disease
- What is being tested?
- carbidopa/levodopa, as prescribed by treating physician
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Feb 2020to 25 Apr 2024
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of Parkinson Disease
- Previously Untreated or treated for <4 weeks
- Mild to Moderate Parkinson disease (Hoehn \& Yahr Stages I-II)
- About to start treatment with a L-Dopa preparation (Sinemet)
Who cannot join
- The presence of other neurologic disease or findings on examination
- Depression: Geriatric Depression Scale score >11
- Use of dopamine agonists or stimulants
- Evidence of a stroke or mass lesion on prior structural brain imaging (MRI or CT)
- Evidence of any confounding medical or psychiatric problem that would preclude task participation.
- Participants with cognitive impairment that might impair their capacity to provide informed consent.
Trial locations and contacts
1 site in 1 country.
About this study
Parkinson disease (PD) is a common disorder in which reduced speed of movement results from inadequate brain production of the chemical dopamine. The most effective treatment for PD is the drug levo-dopa, which partially replaces brain dopamine. Despite decades of successful use, how levo-dopa improves speed of movement in PD is not understood. This observational study recruits participants who have been prescribed levo-dopa by their treating physicians. Before their first dose, immediately after their first dose and later, when their dose has been stabilized, they will engage with the research team to participate in a few simple experiments to measure speed, grip strength, tremor, and stability (on and off of treatment). The purpose of these experiments is to understand how levo-dopa treatment in Parkinson disease enhances movement speed. An important but not understood component of levo-dopa action, the Long Duration Response (LDR), lasts for days to weeks. A basic function of dopamine signaling in the brain is modulation of motivation - the coupling between effort and action values. These experiments will determine if the LDR is associated with relative normalization of motivation function in the brain. The motivation behavior of recently diagnosed PD participants will be examined before and after treatment with levo-dopa to determine if the magnitude of the LDR is correlated with improvements in motivation behavior.
Read the detailed description
Dopamine replacement therapy (DRT) is the standard symptomatic treatment for early to moderate Parkinson disease (PD). In early to moderate PD, the most important DRT component is the Long Duration Response (LDR), a pharmacodynamic effect that builds up over the course of days-weeks and can be induced by dopamine agonists. Despite its effectiveness, DRT actions are poorly understood and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and increasing disability. Improved understanding of the LDR has the potential to prolong the duration of its effects and could have a significant positive effect on clinical practice.
The kinetics of the LDR suggest long-term plastic changes in striatal function. Recent studies of striatal dopamine actions in PD subjects and experimental animals indicate that striatal dopaminergic neurotransmission regulates "vigor," the force, velocity, or amplitude of actions. Vigor is closely allied to the concept that striatal dopaminergic neurotransmission mediates motivation, which involves the assessment of act utility and the appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results suggest that tonic striatal dopamine signaling, mimicked by dopamine agonist administration, is a key determinant of movement vigor. Convergent clinical pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT partially restoring motivational coupling of effort to perceived reward and movement vigor. Prior experiments examining vigor in PD subjects did not take the LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD.
Recent non-human primate work on the control and vigor of saccadic eye movements indicates the existence of basal ganglia circuit changes that stably encode motor action values for prolonged periods. Striatal dopaminergic neurotransmission is critical for establishing this remarkably stable form of value-action coupling. This phenomenon is a plausible circuit level mechanism underlying the LDR.
Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from partial restoration of normal action vigor by reinstating the link between motivation and effort. Our secondary objective is to explore potential mechanisms underlying the LDR. The rationale for these experiments is that better understanding of the LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy.
We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement vigor in response to monetary incentives. Two complementary tasks, one based on modulation of movement velocity and one based on modulation of grip strength, will be employed. To assess whether the recently described stable action-value coupling for saccades is relevant to the LDR, subjects will perform a task that measures saccadic eye movement vigor in response to stable value signals learned prior to LDR induction. Subjects will perform all tasks before and after LDR induction in both the "practical off" and post-acute treatment states.
Specific Aim 1: To use incentive motivation tasks to evaluate the coupling between motivation and movement vigor in recently treated PD subjects before and after LDR induction.
Hypothesis 1A: LDR induction will result in partial restoration of movement vigor in response to monetary incentives in PD subjects in the "practical off" state.
Hypothesis 1B: The magnitude of partially restored movement vigor in response to monetary incentives will correlate with reduced bradykinesia in PD subjects in the "practical off" state.
Hypothesis 1C: Identical effects will be found with an incentive motivation task based on movement amplitude and one based on grip strength.
Specific Aim 2: To use a saccadic eye movement task to assess saccadic eye movement vigor in response to stable value signals in recently treated PD subjects before and after LDR induction.
Hypothesis 2: LDR induction will result in partial restoration of saccadic eye movement vigor in response to previously learned stable value signals in PD subjects in the "practical off" state.
Validation of our hypotheses would have considerable impact by identifying a specific functional process underlying the LDR and a potential mechanism of the LDR. This will facilitate research into LDR mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved symptomatic management of PD.
- Conditions
- Parkinson Disease
- Being tested
- carbidopa/levodopa, as prescribed by treating physician
- Keywords
- Parkinson's Disease
- Medical subject headings
- Parkinson Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
carbidopa/levodopa, as prescribed by treating physicianDrug
Also called Parcopa, Sinemet
There will be 4 measurement states:
at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR).
| Study group | Role | What they receive |
|---|---|---|
| Experiment 1: Primary Outcomes (MDS-UPDRS, Joystick Task, Tapping Speed) | Other | Participants will undergo evaluation of the relationship between the LDR and movement vigor. All participants will undergo standard evaluation with standard clinical rating scales and three outcome measures: Tapping Speed Task; Joystick Movement Task; and completion of MDS-UPDRS.
carbidopa/levodopa, as prescribed by treating physician: There will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR). Receives: Drug: carbidopa/levodopa, as prescribed by treating physician |
| Experiment 2: Primary Outcome (Value Driven Attentional Oculomotor Capture) | Other | Participants will undergo evaluation of the relationship between the LDR and movement vigor. All participants will undergo standard evaluation with standard clinical rating scales and the outcome measure: Grip Strength Task - Measurement of Incentive-Outcome Coupling - Movement Vigor.
carbidopa/levodopa, as prescribed by treating physician: There will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR). Receives: Drug: carbidopa/levodopa, as prescribed by treating physician |
What is being measured
The primary outcome is the main question the study is designed to answer.
Tapping Speed Task - Experiment 1
Measurement of bradykinesia. With the hand most affected by PD, participants were instructed to alternately tap 2 manual counters spaced 20 cm apart as rapidly as possible for 1 minute. The longer participants took to complete the task indicated a higher degree of bradykinesia affecting them. This task was administered over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - No Distractor Value
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - Low Distractor Value
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - High Distractor Value
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Joystick Movement Task - Experiment 1 - Low Incentive
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions:
Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the low incentive.
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Joystick Movement Task - Experiment 1 - Medium Incentive
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions:
Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the medium incentive.
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Joystick Movement Task - Experiment 1 - High Incentive
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions:
Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the high incentive.
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Grip Force Task - Experiment 1 - Low Incentive
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Grip Force Task - Experiment 1 - Medium Incentive
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Grip Force Task - Experiment 1 - High Incentive
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part III - Experiment 1
Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part III, Motor Examination. Scores range from 0 to 86. A higher score indicates worse motor performance. Participants completed this scale at each visit over the course of 4 visits during the following conditions:
Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Measured: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2021
- Study start12 Feb 2020
- Primary completion25 Apr 2024
- Study completion25 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Parkinson DiseaseStudies of the same condition, open and under way.
- More trials run by University of MichiganThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Roger L. Albin, University of Michigan
- Investigators
- Roger Albin, Principal investigator, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04821830
- Sponsor's protocol ID
- HUM00166765
- Other IDs
- R21NS114749
- Status last verified
- Jun 2025
- First submitted
- 10 Mar 2021
- Last updated
- 18 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Vigor and the LDR in Parkinson Disease
- ClinicalTrials.gov ID
- NCT04821830
- Acronym / sponsor ID
- HUM00166765
- Conditions
- Parkinson Disease
- Keywords
- Parkinson's Disease
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- University of MichiganUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- 12 Feb 2020 (actual)
- Primary completion
- 25 Apr 2024 (actual)
- Study completion
- 25 Apr 2024 (actual)
- First posted
- 30 Mar 2021 (actual)
- Results
- Posted 18 Jul 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Parkinson disease (PD) is a common disorder in which reduced speed of movement results from inadequate brain production of the chemical dopamine. The most effective treatment for PD is the drug levo-dopa, which partially replaces brain dopamine. Despite decades of successful use, how levo-dopa improves speed of movement in PD is not understood. This observational study recruits participants who have been prescribed levo-dopa by their treating physicians. Before their first dose, immediately after their first dose and later, when their dose has been stabilized, they will engage with the research team to participate in a few simple experiments to measure speed, grip strength, tremor, and stability (on and off of treatment). The purpose of these experiments is to understand how levo-dopa treatment in Parkinson disease enhances movement speed. An important but not understood component of levo-dopa action, the Long Duration Response (LDR), lasts for days to weeks. A basic function of dopamine signaling in the brain is modulation of motivation - the coupling between effort and action values. These experiments will determine if the LDR is associated with relative normalization of motivation function in the brain. The motivation behavior of recently diagnosed PD participants will be examined before and after treatment with levo-dopa to determine if the magnitude of the LDR is correlated with improvements in motivation behavior.
Detailed description
Dopamine replacement therapy (DRT) is the standard symptomatic treatment for early to moderate Parkinson disease (PD). In early to moderate PD, the most important DRT component is the Long Duration Response (LDR), a pharmacodynamic effect that builds up over the course of days-weeks and can be induced by dopamine agonists. Despite its effectiveness, DRT actions are poorly understood and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and increasing disability. Improved understanding of the LDR has the potential to prolong the duration of its effects and could have a significant positive effect on clinical practice.
The kinetics of the LDR suggest long-term plastic changes in striatal function. Recent studies of striatal dopamine actions in PD subjects and experimental animals indicate that striatal dopaminergic neurotransmission regulates "vigor," the force, velocity, or amplitude of actions. Vigor is closely allied to the concept that striatal dopaminergic neurotransmission mediates motivation, which involves the assessment of act utility and the appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results suggest that tonic striatal dopamine signaling, mimicked by dopamine agonist administration, is a key determinant of movement vigor. Convergent clinical pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT partially restoring motivational coupling of effort to perceived reward and movement vigor. Prior experiments examining vigor in PD subjects did not take the LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD.
Recent non-human primate work on the control and vigor of saccadic eye movements indicates the existence of basal ganglia circuit changes that stably encode motor action values for prolonged periods. Striatal dopaminergic neurotransmission is critical for establishing this remarkably stable form of value-action coupling. This phenomenon is a plausible circuit level mechanism underlying the LDR.
Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from partial restoration of normal action vigor by reinstating the link between motivation and effort. Our secondary objective is to explore potential mechanisms underlying the LDR. The rationale for these experiments is that better understanding of the LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy.
We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement vigor in response to monetary incentives. Two complementary tasks, one based on modulation of movement velocity and one based on modulation of grip strength, will be employed. To assess whether the recently described stable action-value coupling for saccades is relevant to the LDR, subjects will perform a task that measures saccadic eye movement vigor in response to stable value signals learned prior to LDR induction. Subjects will perform all tasks before and after LDR induction in both the "practical off" and post-acute treatment states.
Specific Aim 1: To use incentive motivation tasks to evaluate the coupling between motivation and movement vigor in recently treated PD subjects before and after LDR induction.
Hypothesis 1A: LDR induction will result in partial restoration of movement vigor in response to monetary incentives in PD subjects in the "practical off" state.
Hypothesis 1B: The magnitude of partially restored movement vigor in response to monetary incentives will correlate with reduced bradykinesia in PD subjects in the "practical off" state.
Hypothesis 1C: Identical effects will be found with an incentive motivation task based on movement amplitude and one based on grip strength.
Specific Aim 2: To use a saccadic eye movement task to assess saccadic eye movement vigor in response to stable value signals in recently treated PD subjects before and after LDR induction.
Hypothesis 2: LDR induction will result in partial restoration of saccadic eye movement vigor in response to previously learned stable value signals in PD subjects in the "practical off" state.
Validation of our hypotheses would have considerable impact by identifying a specific functional process underlying the LDR and a potential mechanism of the LDR. This will facilitate research into LDR mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved symptomatic management of PD.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experiment 1: Primary Outcomes (MDS-UPDRS, Joystick Task, Tapping Speed) | Other | Drug: carbidopa/levodopa, as prescribed by treating physicianParticipants will undergo evaluation of the relationship between the LDR and movement vigor. All participants will undergo standard evaluation with standard clinical rating scales and three outcome measures: Tapping Speed Task; Joystick Movement Task; and completion of MDS-UPDRS. carbidopa/levodopa, as prescribed by treating physician: There will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR). |
| Experiment 2: Primary Outcome (Value Driven Attentional Oculomotor Capture) | Other | Drug: carbidopa/levodopa, as prescribed by treating physicianParticipants will undergo evaluation of the relationship between the LDR and movement vigor. All participants will undergo standard evaluation with standard clinical rating scales and the outcome measure: Grip Strength Task - Measurement of Incentive-Outcome Coupling - Movement Vigor. carbidopa/levodopa, as prescribed by treating physician: There will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR). |
Who may qualify
- Ages
- 45 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of Parkinson Disease
- Previously Untreated or treated for <4 weeks
- Mild to Moderate Parkinson disease (Hoehn \& Yahr Stages I-II)
- About to start treatment with a L-Dopa preparation (Sinemet)
Key exclusion criteria (6 listed)
- The presence of other neurologic disease or findings on examination
- Depression: Geriatric Depression Scale score >11
- Use of dopamine agonists or stimulants
- Evidence of a stroke or mass lesion on prior structural brain imaging (MRI or CT)
- Evidence of any confounding medical or psychiatric problem that would preclude task participation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| carbidopa/levodopa, as prescribed by treating physicianAlso: Parcopa, SinemetThere will be 4 measurement states: at baseline prior to chronic treatment initiation (OFF-No LDR); at baseline after a standard, acute oral dose (25/250 carbidopa/L-dopa), referenced in the protocol, but prescribed and provided by their prescribing physician as standard of care initial dosage (ON-No LDR); 2 months after initiation of chronic, stable L-dopa treatment (amounts and sequences as prescribed by treating physicians) but with no L-dopa for 10-12 hours prior to evaluation (Practical OFF- LDR); and after resuming subjects' usual physician-prescribed L-dopa dose (ON-LDR). | Drug | Experiment 1: Primary Outcomes (MDS-UPDRS, Joystick Task, Tapping Speed), Experiment 2: Primary Outcome (Value Driven Attentional Oculomotor Capture) |
Primary outcome
Tapping Speed Task - Experiment 1
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Measurement of bradykinesia. With the hand most affected by PD, participants were instructed to alternately tap 2 manual counters spaced 20 cm apart as rapidly as possible for 1 minute. The longer participants took to complete the task indicated a higher degree of bradykinesia affecting them. This task was administered over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - No Distractor Value
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - Low Distractor Value
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Value Driven Attentional Oculomotor Capture Task - Experiment 2 - High Distractor Value
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants did a saccadic eye movement task involving rapid-eye movements from one point to another to assess the functionality of eye muscles and the brain's ability to control these movements. Participants had an initial training session and then had to complete the task with no distractors, low distractors, and high distractors. This task was administered over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Joystick Movement Task - Experiment 1 - Low Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions: Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the low incentive.
Joystick Movement Task - Experiment 1 - Medium Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions: Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the medium incentive.
Joystick Movement Task - Experiment 1 - High Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
All participants were tasked with pushing a joystick with the hand most affected by PD symptoms in response to monetary incentives. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their movement time in pushing the joystick was measured over the course of 4 visits during the following conditions: Visit 1: Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2: After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3: 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4: After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa). Results reflect participants' response to the high incentive.
Grip Force Task - Experiment 1 - Low Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Grip Force Task - Experiment 1 - Medium Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Grip Force Task - Experiment 1 - High Incentive
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Participants were tasked with modulating their grip strength in response to monetary incentives. With the hand most affected by PD symptoms, participants squeezed a dynamometer. Participants were presented with incentives of low ($5), medium ($10), and high value ($20) on each treatment day, and their time in reaching their maximum grip strength was measured over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part III - Experiment 1
Time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline
Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part III, Motor Examination. Scores range from 0 to 86. A higher score indicates worse motor performance. Participants completed this scale at each visit over the course of 4 visits during the following conditions: Visit 1. Baseline prior to chronic treatment initiation (Treatment Naïve Subject); Visit 2. After the initial, standard, acute oral dosage (SDR: Treatment Naïve Subject After Acute LDopa); Visit 3. 2-4 months after start of chronic treatment following Visit 2, stable LDopa treatment (as prescribed by treating physicians), but with no LDopa for 10-12 hours prior to Visit 3 (LDR: Chronically Treated - "Practical Off" State); and Visit 4. After resuming participants' usual physician-prescribed LDopa dose (SDR + LDR: Chronically Treated - After Usual LDopa).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Related trials for Parkinson Disease
Not yet recruitingPhase 1/2
STAR0602 With Nivolumab in Non Small Cell Lung Cancer and in Metastatic Castrate-Resistant Prostate Cancer, and STAR0602 Alone in Thymic Carcinoma
NSCLC, Non-Small Cell Lung Cancer
Enrolling by invitationObservational study
Early Molecular Biomarkers for Differentiating Parkinsonian Syndromes
PARKINSON DISEASE (Disorder), Atypical Parkinsonism
RecruitingPhase 3
A Clinical Study of Sacituzumab Tirumotecan (MK-2870) in Combination With Pembrolizumab (MK-3475) as First-line Maintenance Treatment of Cervical Cancer (MK-2870-036/TroFuse-036/GOG-3123/ENGOT-cx22)
Cervical Cancer
Active, not recruitingPhase 1/2
Clinical Safety and Efficacy of Umbilical Cord Mesenchymal Stromal Cells-derived Exosomes in Patients With Parkinson's Disease
Parkinson Disease (PD)
Active, not recruitingObservational study
Adaptive DBS to Offset STN Dysregulation During Exercise in PD
Parkinson Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roger Albin principal investigator
University of Michigan
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing carbidopa/levodopa, as prescribed by treating physician in people with Parkinson Disease, run by University of Michigan at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tapping Speed Task - Experiment 1 (time frame: Visit 1 at Baseline, Visit 2 up to 2 weeks after baseline, Visit 3 up to 2-4 months after baseline, and Visit 4 up to 4 months after baseline). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2025.