Parkinson Disease
Conditions
Keywords
Parkinson, Botox, Tremor
Brief summary
Purpose: Rest tremor in Parkinson's disease is notoriously difficult to treat through pharmacological measures, currently only predictably attenuated by the invasive deep brain stimulation surgery. The investigators hope to find some predictable and clinically meaningful attenuation of tremor with targeted use of onabotulinum toxin on muscles involved in creating the tremor. Participants: 16 subjects who meet United Kingdom (UK) brain bank criteria for Parkinson's disease with medically refractory rest tremor of at least 3 cm amplitude. Procedures (methods): Subjects will be blinded to receive either sham saline injection versus onabotulinum toxin injections directed to muscle groups felt to be clinically involved in causing the oscillatory movement of the tremor. Assessment of tremor severity and functional improvement from baseline after injection will occur within group (i.e. each subject will serve as their own control). Hypotheses: 1\. (A) Onabotulinumtoxin A significantly attenuates the amplitude of medically-refractory rest tremor of the upper limb in Parkinson's patients as compared to sham injections; as measured by reduction in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) tremor subscore. 1\. (B) Onabotulinumtoxin A significantly improves the limb function of Parkinson's patients with medically-refractory rest tremor of the upper limb as compared to sham injections; as measured by an increase in Action Research Arm Test (ARAT) scores.
Detailed description
For purposes of properly identifying muscles intended for injection, a portable electromyography will be attached to an appropriate gauge electromyography-guided botulinum toxin needle, which in turn will be used to hear/see motor evoked potentials (MEPs). Subjects will be asked to activate the muscle while needle is inserted to ensure proper placement of the needle in the desired muscle prior to injection of study solution.
Interventions
DRUGOnabotulinumtoxin A Injection
Reconstituted 10 units/0.1 mL. Administered intramuscular once
OTHERPlacebo
0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once.
Sponsors
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blinded study whereby the subject, the movement disorder specialist injecting neurotoxin, and the movement disorder specialist rating the patient will be unaware of the solution injected and/or planned for injection same day. To ensure that the injecting specialist is blinded to the solution, syringes will be premixed by a separate member of the research team and de-identified of any possible labels that would indicate the properties of the solution being administered to the subject.
Intervention model description
The study will comprise of a double blinded, crossover study where the subjects will serve as their own controls. There will be no medication changes made to Parkinson's disease medications throughout the subjects' participation in the study.
Eligibility
Sex/Gender
ALL
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. At least 45 years of age, and no more than 80 years of age. 2. Meet UK Parkinson's disease brain bank diagnostic criteria 3. Have clinical evidence of rest tremor of one or both upper extremities defined as involuntary, rhythmic oscillations about any joint within the upper extremities 4. Rest tremor amplitude must be at minimum 3 cm as determined by expert opinion by a movement disorders specialist. Confirmation of amplitude measurement will be obtained from the Px1 prior to active participation in the study but will not be used for inclusion/exclusion in study participation. 5. Rest tremor must be historically refractory to at least 2 categories of medications typically used as anti-parkinsonian agents including levodopa formulations, dopamine agonists, amantadine, and anticholinergics. 6. Participants must be able to make no changes to their anti-parkinsonian medications for 150 days (study duration). Ability and safety to do so must also be determined by the participant's treating physician and confirmed in writing prior to participating. 7. Able to provide informed consent
Exclusion criteria
1. History of having undergone botulinum toxin injections for any other condition previously 2. Allergy to carbidopa or levodopa. 3. Prescreening Montreal Cognitive Assessment (MoCA) score less than 22 4. Prescreening muscle weakness as determined by Medical Research Council grade less than 5/5 on direct testing in the upper limb afflicted with rest tremor. 5. Pregnancy: documentation of non-pregnancy by urine pregnancy test will be obtained from all women of child-bearing potential prior to participation 6. Infection at the proposed injection site 7. Those with a pre-existing, concomitant neuromuscular disorder 8. Compromised respiratory function 9. History of having undergone deep brain stimulation surgery for any condition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the MDS-UPDRS Tremor Subscore | Prior to onabotulinumtoxinA injection and at 30 days after injection | The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III's tremor subscore (3.17). The subscale has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse tremor/motor function. Larger differences will infer greater effect size for the intervention. Score drops over time imply improvement in tremor/motor function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the ARAT Score | Prior to onabotulinumtoxinA injection and at 30 days after injection | The Action Research Arm Test (ARAT) is an evaluated measure to assess specific changes in limb function after neurologic sequelae. It assesses a person's ability to handle objects differing in size, weight and shape and therefore can be considered to be an arm-specific measure of activity limitation. The ARAT is a 19 item measure divided into 4 sub-tests (grasp, grip, pinch, and gross arm movement). Performance on each item is rated on a 4-point ordinal scale: 3: Performs test normally 2: Completes test, but takes abnormally long or has great difficulty 1: Performs test partially 0: Can perform no part of test. The maximum score on the ARAT is 57 points (possible range 0 to 57). Higher ARAT scores reflect greater preservation of function in tested arm. Larger differences will infer greater effect sizes for the intervention. Score drops over time imply worsening limb function. |
| Correlation Between MDS-UPDRS Tremor Subscore and Px1 Tremor Amplitude | At Visit 1, prior to 1st injection through Visit 4, 30 days after last injection | MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used is Part III's tremor subscore 3.17. The subscale has a 0-4 rating: (0=no tremor, 1=\<1cm, 2=1-3 cm, 3=3-10 cm, 4=\>10cm). Higher scores reflect worse tremor amplitude. Larger differences infer greater effect size. The Px1 is a novel, external measuring device using motion-capture technology to determine the frequency, direction and amplitude of movement between hand joints. Movement is captured without ever applying direct pressure on the limb. Output includes tremor frequency in Hz and distance traveled by a hand joint as compared to other joints on the hand in cm. The largest tremor amplitude measured by Px1 was acquired 3x/visit, values averaged then compared with the amplitude range corresponding to MDS-UPDRS tremor subscore. This process was repeated for all subjects for Visits 1-4 comparing all values using Spearman correlation coefficient. |
| Change in Tremor Amplitude in Centimeters (cm) as Measured by Px1 | Prior to onabotulinumtoxinA injection and at 30 days after injection | The Px1 is a novel, external measuring device which uses motion-capture technology to determine the frequency, direction, and amplitude of movement between joints within the hand. Oscillatory movement is captured using a camera system and without ever applying any direct pressure upon the limb. Output includes tremor frequency in (Hertz Hz), and distance traveled by a hand joint as compared to other joints on the hand in centimeters (cm) |
| Change in Tremor Frequency in Hertz (Hz) as Measured by Px1 | Prior to onabotulinumtoxinA injection and at 30 days after injection | The Px1 is a novel, external measuring device which uses motion-capture technology to determine the frequency, direction, and amplitude of movement between joints within the hand. Oscillatory movement is captured using a camera system and without ever applying any direct pressure upon the limb. Output includes tremor frequency in (Hertz Hz), and distance traveled by a hand joint as compared to other joints on the hand in centimeters (cm) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OnabotulinumtoxinA Injection, Then Placebo Participants first receive OnabotulinumtoxinA Injection and following a 3-month washout, they receive Placebo
OnabotulinumtoxinA Injection: Reconstituted 10 units/0.1 mL. Administered intramuscular once
Placebo: 0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once. | 7 |
| Placebo, Then OnabotulinumtoxinA Injection Participants first receive placebo injection and following a 3-month washout, they receive OnabotulinumtoxinA Injection.
OnabotulinumtoxinA Injection: Reconstituted 10 units/0.1 mL. Administered intramuscular once
Placebo: 0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once. | 9 |
| Total | 16 |
Baseline characteristics
| Characteristic | Placebo, Then OnabotulinumtoxinA Injection | Total | OnabotulinumtoxinA Injection, Then Placebo |
|---|---|---|---|
| Age, Continuous | 64.7 years | 65.5 years | 65.7 years |
| Chosen Limb for Study Left Arm | 4 Participants | 7 Participants | 3 Participants |
| Chosen Limb for Study Right Arm | 5 Participants | 9 Participants | 4 Participants |
| Levodopa Equivalent Dosing (LED) | 162.22 mg STANDARD_DEVIATION 103.53 | 134.25 mg STANDARD_DEVIATION 89.22 | 98.29 mg STANDARD_DEVIATION 54.1 |
| Mean Number of Parkinson's Medications Failed Prior to Enrollment | 3.0 Failed Medications STANDARD_DEVIATION 1.22 | 3.13 Failed Medications STANDARD_DEVIATION 1.2 | 3.29 Failed Medications STANDARD_DEVIATION 1.25 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 9 Participants | 16 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 6 / 16 | 2 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Change in the MDS-UPDRS Tremor Subscore
The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used in this study is Part III's tremor subscore (3.17). The subscale has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse tremor/motor function. Larger differences will infer greater effect size for the intervention. Score drops over time imply improvement in tremor/motor function.
Time frame: Prior to onabotulinumtoxinA injection and at 30 days after injection
Population: One participant was unavailable to complete assessment during defined window.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OnabotulinumtoxinA Injection | Change in the MDS-UPDRS Tremor Subscore | 0.25 score on a scale |
| Placebo | Change in the MDS-UPDRS Tremor Subscore | 0.27 score on a scale |
p-value: 0.5Regression, Linear
Secondary
Change in the ARAT Score
The Action Research Arm Test (ARAT) is an evaluated measure to assess specific changes in limb function after neurologic sequelae. It assesses a person's ability to handle objects differing in size, weight and shape and therefore can be considered to be an arm-specific measure of activity limitation. The ARAT is a 19 item measure divided into 4 sub-tests (grasp, grip, pinch, and gross arm movement). Performance on each item is rated on a 4-point ordinal scale: 3: Performs test normally 2: Completes test, but takes abnormally long or has great difficulty 1: Performs test partially 0: Can perform no part of test. The maximum score on the ARAT is 57 points (possible range 0 to 57). Higher ARAT scores reflect greater preservation of function in tested arm. Larger differences will infer greater effect sizes for the intervention. Score drops over time imply worsening limb function.
Time frame: Prior to onabotulinumtoxinA injection and at 30 days after injection
Population: Two participants were unavailable to complete assessments during defined window.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OnabotulinumtoxinA Injection | Change in the ARAT Score | 53.67 score on a scale |
| Placebo | Change in the ARAT Score | 55.47 score on a scale |
Secondary
Change in Tremor Amplitude in Centimeters (cm) as Measured by Px1
The Px1 is a novel, external measuring device which uses motion-capture technology to determine the frequency, direction, and amplitude of movement between joints within the hand. Oscillatory movement is captured using a camera system and without ever applying any direct pressure upon the limb. Output includes tremor frequency in (Hertz Hz), and distance traveled by a hand joint as compared to other joints on the hand in centimeters (cm)
Time frame: Prior to onabotulinumtoxinA injection and at 30 days after injection
Population: Given that the Px1 tool was simultaneously undergoing validation during the trial, using the tool to determine the differences in tremor amplitude was deemed inappropriate.
Secondary
Change in Tremor Frequency in Hertz (Hz) as Measured by Px1
The Px1 is a novel, external measuring device which uses motion-capture technology to determine the frequency, direction, and amplitude of movement between joints within the hand. Oscillatory movement is captured using a camera system and without ever applying any direct pressure upon the limb. Output includes tremor frequency in (Hertz Hz), and distance traveled by a hand joint as compared to other joints on the hand in centimeters (cm)
Time frame: Prior to onabotulinumtoxinA injection and at 30 days after injection
Population: Given that the Px1 tool was simultaneously undergoing validation during the trial, using the tool to determine the differences in tremor frequency was deemed inappropriate.
Secondary
Correlation Between MDS-UPDRS Tremor Subscore and Px1 Tremor Amplitude
MDS-UPDRS retains the four-scale structure with a reorganization of the various subscales. The subscale used is Part III's tremor subscore 3.17. The subscale has a 0-4 rating: (0=no tremor, 1=\<1cm, 2=1-3 cm, 3=3-10 cm, 4=\>10cm). Higher scores reflect worse tremor amplitude. Larger differences infer greater effect size. The Px1 is a novel, external measuring device using motion-capture technology to determine the frequency, direction and amplitude of movement between hand joints. Movement is captured without ever applying direct pressure on the limb. Output includes tremor frequency in Hz and distance traveled by a hand joint as compared to other joints on the hand in cm. The largest tremor amplitude measured by Px1 was acquired 3x/visit, values averaged then compared with the amplitude range corresponding to MDS-UPDRS tremor subscore. This process was repeated for all subjects for Visits 1-4 comparing all values using Spearman correlation coefficient.
Time frame: At Visit 1, prior to 1st injection through Visit 4, 30 days after last injection
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OnabotulinumtoxinA Injection | Correlation Between MDS-UPDRS Tremor Subscore and Px1 Tremor Amplitude | 0.6225 Spearman Correlation Coefficient |
| Placebo | Correlation Between MDS-UPDRS Tremor Subscore and Px1 Tremor Amplitude | 0.4354 Spearman Correlation Coefficient |