Parkinson's Disease
Conditions
Keywords
Rasagiline
Brief summary
Parkinson's disease (PD) is a neurodegenerative brain disorder that impairs the ability to perform functions such as grooming, dressing, cooking, and other activities of daily living. PD affected between 4.1 and 4.6 million people worldwide in 2005, and it is projected that up to 9.3 million people will be affected by 2030. Although current pharmacological therapies provide beneficial effects on motor symptoms of the disease (tremor, rigidity, and bradykinesia), intolerable disability eventually develops in most patients. A disease-modifying therapy that slows disease progression is a major unmet medical need in PD. Numerous agents have neuroprotective effects in pre-clinical laboratory models, but none have been shown to have indisputable disease-modifying effects in clinical trials for patients with PD. The purpose of this research study is to investigate how the brain and motor behavior changes in PD over time in response to rasagiline which is a monoamine oxidase-B(MAO-B) inhibitor. The drug rasagiline will be tested in this study as the MAO-B inhibitor. Rasagiline has been prescribed for many years to treat symptomatic Parkinson's disease. It is FDA approved for the treatment of Parkinson's disease but has not been shown to slow disease progression. The outcome and impact of this study will provide the first evaluation of MAO-B inhibitors at slowing the progression of the nigrostriatal pathway using advanced Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) methods in PD.
Detailed description
Participants will receive baseline testing to confirm a diagnosis of Parkinsonism and to determine eligibility in the research study. Half of the participants in this study will be in a group that will receive the study drug (rasagiline), and half will be in a group that will receive a placebo. A placebo is a pill that is made to look like the study drug, but it does not contain any active ingredients. A computer algorithm will randomly decide group assignment (like the flip of a coin). The study drug will be provided at the end of the first visit. The participants will not know which study drug is received, placebo or rasagiline. During the research study the following test may occur: (1) questionnaires about quality of life and depression; (2) tests to measure strength and motor function; (3) tests to measure cognition; (4) orientation session to learn a precision gripping task; (5) functional MRI scan of the brain; (6) structural MRI scan of the brain.
Interventions
DRUGRasagiline
Rasagiline will be taken for one year at the dose of 1mg a day. and subjects will undergo functional and structural brain imaging to determine if rasagiline is slowing the progression of Parkinson's Disease in the brain.
OTHERPlacebo
A placebo tablet will be taken for one year, once a day, and at the same dose of 1mg. subjects will undergo functional and structural brain imaging to be compared with the group taking the rasagiline intervention.
DEVICEMagnetic Resonance Imaging
This test will be performed at baseline and one year.
DEVICEfunctional Magnetic Resonance Imaging
This test will be performed at baseline and one year.
OTHERPhysical Function Performance Test
This test will be performed at baseline and one year.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 77 Years
Healthy volunteers
No
Inclusion criteria
* 96 patients with clinically diagnosed PD. For the PD diagnosis, we will use the University of Kentucky PD brain bank diagnostic criteria implemented by a movement disorders trained neurologist. Only early stage PD within 5 years of diagnosis who have never taken rasagiline will be included. 5 years since diagnosis was chosen to focus on early stages of PD, where MAO-B inhibitors have shown the most promise. PD are eligible to participate if they are age 40-77, Hoehn and Yahr stage \< or equal to 2 when on medication, and able and willing to sign informed consent to be randomized to the placebo or active drug arm.
Exclusion criteria
* As necessitated by the risks of Magnetic Resonance Imaging, patients who have any type of implanted electrical device (such as a cardiac pacemaker or a neurostimulator), or a certain type of metallic clip in their body (i.e., an aneurysm clip in the brain), are not eligible for participation in the MRI portion of the study. * Individuals who are claustrophobic will also be excluded from participation. * Women who are or might be pregnant and nursing mothers are not eligible. Pregnancy tests will be carried out for each female subject prior to the MRI scan. * Individuals with psychiatric disorders or dementia will be excluded, along with other neurologic and orthopedic problems that impair hand movements and walking. * Individuals who have a history metalworking involving cutting processes such as grinding, filing, shaving, and threading, will need radiological clearance to participate in this study. Specifically, individuals who report a history of metalworking will be referred to Radiology at Shands University of Florida(UF) for an orbitofrontal x-ray. In addition, individuals who have sustained an eye injury involving metal will also be referred to Radiology at Shands UF for an orbitofrontal x-ray. Shands at UF will provide a written report stating whether the individual is safe for imaging at 3 Tesla. All expenses related to this procedure will be covered by the PI. * Patients with a prior stroke or brain tumor are excluded. Patients will be excluded if they are unwilling to comply with the study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Free-water Accumulation in the Substantia Nigra | Baseline and one-year | 12-month study in PD to watch the effect of an Monoamine Oxidase-B inhibitor on the progressive increase of free-water accumulation in the substantia nigra. Recently, free-water diffusion MRI analysis using a bi-tensor model was developed to explicitly estimate the contribution of freely diffusing water molecules within the voxel. This free-water measure is expected to increase with atrophy-based neurodegeneration. Since substantia nigra degeneration occurs mostly in the posterior region of the substantia nigra in PD (ie. ventrolateral tier), we tested the hypothesis that free-water would be elevated in the posterior substantia nigra of PD. |
| Change in Blood Oxygen Level-dependent(BOLD) Signal in the Posterior Putamen, M1, and Supplementary Motor Area(SMA). | Baseline and one-year | 12-month study in PD to watch the effect of an MAO-B inhibitor on BOLD signal in the posterior putamen, M1, and SMA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Parkinson's Disease Motor Symptoms and Bradykinesia | Baseline and one-year | Motor testing batteries such as the Purdue Pegboard Test will be administered to measure changes in the progression of the PD motor symptoms and bradykinesia. |
| Changes Between the Groups on fMRI | Changes from baseline to 1 year | Participants will use their hand to squeeze an MRI compatible grip force transducer in the MRI unit. |
Countries
United States
Participant flow
Pre-assignment details
96 participants diagnosed with PD signed the informed consent document for the study. 6 of these individuals did not complete the study protocol for a variety of reasons: 1 person revealed he had a prior stroke so he was disqualified at the visit, 2 people were excluded due to space restrictions in the MRI, and 3 people withdrew due to claustrophobia related to the MRI. Therefore, out of the 96 people who signed the consent (were enrolled), only 90 peoples' data were included/randomized.
Participants by arm
| Arm | Count |
|---|---|
| Rasagiline This group will receive a 1 mg rasagiline tablet to be taken once daily for one year. In addition, the following test will be performed: a Magnetic Resonance Imaging (MRI), functional Magnetic Resonance Imaging (fMRI), the Montreal Cognitive Assessment, Stroop, Digit Span, Hopkins Verbal Learning Test, Brief Test of Attention, Beck Depression Index, Hamilton Anxiety and Depression Rating Scales, Physical Function Performance Test, and Epworth Sleepiness Scale.
Rasagiline: Rasagiline will be taken for one year at the dose of 1mg a day. and subjects will undergo functional and structural brain imaging to determine if rasagiline is slowing the progression of Parkinson's Disease in the brain.
Magnetic Resonance Imaging: This test will be performed at baseline and one year.
functional Magnetic Resonance Imaging: This test will be performed at baseline and one year.
Physical Function Performance Test: This test will be performed at baseline and one year. | 45 |
| Placebo This group will receive a placebo tablet in the same forum as the rasagiline tablet to be taken once daily for one year. In addition, the following test will be performed: a Magnetic Resonance Imaging (MRI), functional Magnetic Resonance Imaging (fMRI), the Montreal Cognitive Assessment, Stroop, Digit Span, Hopkins Verbal Learning Test, Brief Test of Attention, Beck Depression Index, Hamilton Anxiety and Depression Rating Scales, Physical Function Performance Test, and Epworth Sleepiness Scale.
Placebo: A placebo tablet will be taken for one year, once a day, and at the same dose of 1mg. subjects will undergo functional and structural brain imaging to be compared with the group taking the rasagiline intervention.
Magnetic Resonance Imaging: This test will be performed at baseline and one year.
functional Magnetic Resonance Imaging: This test will be performed at baseline and one year.
Physical Function Performance Test: This test will be performed at baseline and one year. | 45 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Rasagiline | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 27 Participants | 51 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 39 Participants | 21 Participants |
| Age, Continuous | 65.02 years STANDARD_DEVIATION 7.77 | 64.23 years STANDARD_DEVIATION 8.13 | 63.44 years STANDARD_DEVIATION 8.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants | 86 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Hamilton Anxiety Rating Scale | 8.53 units on a scale STANDARD_DEVIATION 8.04 | 9.64 units on a scale STANDARD_DEVIATION 8.02 | 10.69 units on a scale STANDARD_DEVIATION 7.94 |
| Hamilton Rating Scale for Depression | 5.09 units on a scale STANDARD_DEVIATION 4.38 | 6.06 units on a scale STANDARD_DEVIATION 5.33 | 7.02 units on a scale STANDARD_DEVIATION 6.02 |
| Montreal Cognitive Assessment | 26.64 units on a scale STANDARD_DEVIATION 2.17 | 26.23 units on a scale STANDARD_DEVIATION 2.5 | 25.82 units on a scale STANDARD_DEVIATION 2.77 |
| Movement Disorders Society UPDRS | 29.62 units on a scale STANDARD_DEVIATION 10.87 | 31.19 units on a scale STANDARD_DEVIATION 11.71 | 32.76 units on a scale STANDARD_DEVIATION 12.42 |
| Parkinson's Disease Questionnaire (PDQ-39) | 18.28 units on a scale STANDARD_DEVIATION 18.84 | 22.19 units on a scale STANDARD_DEVIATION 19.9 | 25.93 units on a scale STANDARD_DEVIATION 20.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 43 Participants | 86 Participants | 43 Participants |
| Region of Enrollment United States | 45 Participants | 90 Participants | 45 Participants |
| Sex: Female, Male Female | 16 Participants | 29 Participants | 13 Participants |
| Sex: Female, Male Male | 29 Participants | 61 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 45 |
| other Total, other adverse events | 12 / 45 | 9 / 45 |
| serious Total, serious adverse events | 0 / 45 | 0 / 45 |
Outcome results
Primary
Change in Blood Oxygen Level-dependent(BOLD) Signal in the Posterior Putamen, M1, and Supplementary Motor Area(SMA).
12-month study in PD to watch the effect of an MAO-B inhibitor on BOLD signal in the posterior putamen, M1, and SMA.
Time frame: Baseline and one-year
Population: The values below represent the BOLD signal in SMA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Change in Blood Oxygen Level-dependent(BOLD) Signal in the Posterior Putamen, M1, and Supplementary Motor Area(SMA). | -0.054 arbitrary units (A.U.s) | Standard Deviation 0.315 |
| Placebo | Change in Blood Oxygen Level-dependent(BOLD) Signal in the Posterior Putamen, M1, and Supplementary Motor Area(SMA). | -0.086 arbitrary units (A.U.s) | Standard Deviation 0.251 |
Primary
Change in Free-water Accumulation in the Substantia Nigra
12-month study in PD to watch the effect of an Monoamine Oxidase-B inhibitor on the progressive increase of free-water accumulation in the substantia nigra. Recently, free-water diffusion MRI analysis using a bi-tensor model was developed to explicitly estimate the contribution of freely diffusing water molecules within the voxel. This free-water measure is expected to increase with atrophy-based neurodegeneration. Since substantia nigra degeneration occurs mostly in the posterior region of the substantia nigra in PD (ie. ventrolateral tier), we tested the hypothesis that free-water would be elevated in the posterior substantia nigra of PD.
Time frame: Baseline and one-year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Change in Free-water Accumulation in the Substantia Nigra | 0.0009 arbitrary units (A.U.s) | Standard Deviation 0.01 |
| Placebo | Change in Free-water Accumulation in the Substantia Nigra | 0.0041 arbitrary units (A.U.s) | Standard Deviation 0.01 |
Secondary
Changes Between the Groups on fMRI
Participants will use their hand to squeeze an MRI compatible grip force transducer in the MRI unit.
Time frame: Changes from baseline to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Changes Between the Groups on fMRI | -0.054 unitless | Standard Deviation 0.315 |
| Placebo | Changes Between the Groups on fMRI | -0.086 unitless | Standard Deviation 0.251 |
Secondary
Changes in Parkinson's Disease Motor Symptoms and Bradykinesia
Motor testing batteries such as the Purdue Pegboard Test will be administered to measure changes in the progression of the PD motor symptoms and bradykinesia.
Time frame: Baseline and one-year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rasagiline | Changes in Parkinson's Disease Motor Symptoms and Bradykinesia | 1.04 count of pegs | Standard Deviation 3.15 |
| Placebo | Changes in Parkinson's Disease Motor Symptoms and Bradykinesia | 0.689 count of pegs | Standard Deviation 3.94 |