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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Onabotulinumtoxin A Injection, then Placebo | Experimental | Participants first receive Onabotulinumtoxin A Injection and following a 3-month washout, they receive Placebo |
|
| Placebo, then Onabotulinumtoxin A Injection | Experimental | Participants first receive placebo injection and following a 3-month washout, they receive Onabotulinumtoxin A Injection. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Onabotulinumtoxin A Injection | Drug | Reconstituted 10 units/0.1 mL. Administered intramuscular once |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Prior to onabotulinumtoxinA injection and at 30 days after injection |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel A Roque, MD | University of North Carolina, Chapel Hill | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UNC Hospitals Neurology Clinic | Chapel Hill | North Carolina | 27517 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo, Then OnabotulinumtoxinA Injection | Participants first receive placebo injection and following a 3-month washout, they receive Onabotulinumtoxin A 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (30 Days) |
| |||||||||||||
| Washout (90 Days From 1st Intervention) |
| |||||||||||||
| Second Intervention (30 Days) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | One participant was unavailable to complete assessment during defined window. | Posted | Mean | 95% Confidence Interval | score on a scale | Prior to onabotulinumtoxinA injection and at 30 days after injection |
|
Adverse events were included starting with the Screening Visit up to and including Visit 5, a total of approximately 150 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Onabotulinumtoxin A Injection | Participants receive Onabotulinumtoxin A Injection. OnabotulinumtoxinA Injection: Reconstituted 10 units/0.1 mL. Administered intramuscular once |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Weakness of Injected Limb | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel Roque, MD | University of North Carolina at Chapel Hill | 919-966-8178 | droque@neurology.unc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 3, 2018 | Jun 9, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| D014202 | Tremor |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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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.
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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.
|
| Placebo | Other | 0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once. |
|
|
| Prior to onabotulinumtoxinA injection and at 30 days after injection |
| 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. | At Visit 1, prior to 1st injection through Visit 4, 30 days after last injection |
| 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) | Prior to onabotulinumtoxinA injection and at 30 days after injection |
| 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) | Prior to onabotulinumtoxinA injection and at 30 days after injection |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| BG001 |
| 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Chosen Limb for Study | Count of Participants | Participants |
|
| Mean Number of Parkinson's Medications Failed Prior to Enrollment | Mean | Standard Deviation | Failed Medications |
|
| Levodopa Equivalent Dosing (LED) | Levodopa Equivalent Dosing (LED) gives a rough way to compare two Parkinson's medications. All medications for Parkinson's can be compared in level of effect to Levodopa, the most consistently used medication for this disease. | Mean | Standard Deviation | mg |
|
Participants receive OnabotulinumtoxinA Injection. OnabotulinumtoxinA Injection: Reconstituted 10 units/0.1 mL. Administered intramuscular once |
| OG001 | Placebo | Participants receive placebo injection. Placebo: 0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once. |
|
|
|
| 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. | Two participants were unavailable to complete assessments during defined window. | Posted | Mean | 95% Confidence Interval | score on a scale | Prior to onabotulinumtoxinA injection and at 30 days after injection |
|
|
|
| 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. | Posted | Number | Spearman Correlation Coefficient | At Visit 1, prior to 1st injection through Visit 4, 30 days after last injection |
|
|
|
| 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) | 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. | Posted | Prior to onabotulinumtoxinA injection and at 30 days after injection |
|
|
| 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) | 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. | Posted | Prior to onabotulinumtoxinA injection and at 30 days after injection |
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| 6 |
| 16 |
| EG001 | Placebo | Participants receive placebo injection. Placebo: 0.9% normal saline solution, mimicking Botox injection paradigm. Administered intramuscular once. | 0 | 16 | 0 | 16 | 2 | 16 |
| Pain of Injected Limb | Injury, poisoning and procedural complications | Systematic Assessment |
|
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| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| D020820 | Dyskinesias |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006867 |
| Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |