Effectiveness of Botox on Reducing Rest Tremor in Parkinson's Disease

Phase 2

Completed

Conditions: Parkinson Disease

Interventions: Drug: Onabotulinumtoxin A Injection
Other: Placebo

Registration Number: NCT03301272

Lead Sponsor: University of North Carolina, Chapel Hill

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

Inclusion Criteria

At least 45 years of age, and no more than 80 years of age.
Meet UK Parkinson's disease brain bank diagnostic criteria
Have clinical evidence of rest tremor of one or both upper extremities defined as involuntary, rhythmic oscillations about any joint within the upper extremities
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.
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.
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.
Able to provide informed consent

Exclusion Criteria

History of having undergone botulinum toxin injections for any other condition previously
Allergy to carbidopa or levodopa.
Prescreening Montreal Cognitive Assessment (MoCA) score less than 22
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.
Pregnancy: documentation of non-pregnancy by urine pregnancy test will be obtained from all women of child-bearing potential prior to participation
Infection at the proposed injection site
Those with a pre-existing, concomitant neuromuscular disorder
Compromised respiratory function
History of having undergone deep brain stimulation surgery for any condition

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Onabotulinumtoxin A Injection, then Placebo	Onabotulinumtoxin A Injection	Participants first receive Onabotulinumtoxin A Injection and following a 3-month washout, they receive Placebo
Placebo, then Onabotulinumtoxin A Injection	Placebo	Participants first receive placebo injection and following a 3-month washout, they receive Onabotulinumtoxin A Injection.
Onabotulinumtoxin A Injection, then Placebo	Placebo	Participants first receive Onabotulinumtoxin A Injection and following a 3-month washout, they receive Placebo
Placebo, then Onabotulinumtoxin A Injection	Onabotulinumtoxin A Injection	Participants first receive placebo injection and following a 3-month washout, they receive Onabotulinumtoxin A Injection.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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)