Tremor
Conditions
Keywords
Kinematics, Botulinum toxin type A
Brief summary
The present study attempts to fill a critical knowledge gap of BoNT A in tremor management by studying the efficacy of IncobotulinumtoxinA (Xeomin®) injection for hand tremor in essential tremor and idiopathic Parkinson disease using data regarding composition of tremor obtained through sophisticated, yet clinically accessible multi-sensor based kinematic information.
Detailed description
Current pharmacological agents used to treat Parkinson disease (PD) tremor and essential tremor (ET) provide suboptimal benefit and are commonly associated with significant adverse effects. Botulinum toxin type A (BoNT-A) has been shown to be effective for wrist tremor though functionally bothersome muscle weakness frequently occurs. This is the longest study to date demonstrating that BoNT-A therapy coupled with kinematic guidance can provide efficacious outcomes for upper limb tremor with minimized unwanted weakness. A total of 28 PD and 24 ET participants with bothersome, disabling tremor, received six serial BoNT-A treatments every 16 weeks starting at week 0 with a follow-up visit 6 weeks following a treatment, totaling 96 weeks. Clinical scales, including Fahn-Tolosa-Marin tremor rating scale (FTM), and sensor-based tremor assessments were conducted at each visit. Kinematics was utilized to identify which arm muscles contributed to the tremulous movements and the experienced injector used clinical expertise in determining BoNT-A dosages. Following BoNT-A treatment, clinical ratings of tremor severity and functional ability (FTM) showed significant improvements following the first treatment which was maintained up to week 96 in PD and ET. Kinematics detected a significant reduction in PD and ET tremor amplitudes by 70% and 76% over the treatment course, respectively. By objectively distinguishing tremulous muscles and tremor severity, adverse effects were limited to mild perceived weakness by participants in injected muscles during follow-ups. Following the fourth treatment, BoNT-A dosages in flexor and extensor wrist muscles and biceps were reduced for those experiencing residual weakness which ultimately did not interfere with tremor relief or arm function. Kinematics is an objective method that can aid clinicians in assessing and determining optimal BoNT-A parameters to alleviate both PD and ET tremor. BoNT-A injections are tolerable and effective when focal therapy regimens are determined and optimized kinematically over a long-term
Interventions
DRUGBoNT-A
A serotype of botulinum toxins that has specificity for cleavage of SYNAPTOSOMAL-ASSOCIATED PROTEIN 25 (SNAP-25). BoNT-A's pharmacological action is to inhibit the release of acetylcholine from the neuromuscular junction. BoNT-A peripherally applied using optimal parameters by intramuscular injections to treat tremor in the most bothersome upper extremity every 16 weeks over 96 weeks. The study will be extended for those participants who benefited and will receive treatment every 12 weeks over 96 weeks. BoNT-A dose will range from 50-300 U per arm.
Sponsors
Western University, Canada
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Consenting male and female participants, aged 18 years to 80 years * PD individuals diagnosed by UK Brain Bank Criteria with stage H&Y2-3 disease or ET with hand tremor in their motor dominant hand * Stable IPD/ET medication management for the 6 month duration prior to their enrollment in the study * Individuals with IPD will be eligible for the study only if tremor is their primary and most bothersome symptom as determined by clinical exam and patient report * Participants who are botulinum toxin naïve for tremor management
Exclusion criteria
* History of stroke * Muscle weakness or any related compartmental muscle syndrome * Smoking * Offending medications (Lithium, valproate, steroids, amiodarone, beta-adrenergic agonists (e.g. salbutamol)) * Contradictions per the Xeomin® drug monograph * Patients prescribed zonisamide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale) | 0 to 96 weeks | Improvement in hand tremor as determined by a reduction of \>8 points on a standardized clinical assessment tool (Fahn-Tolosa-Marin Tremor Assessment Scale) pre and post Xeomin® injection using kinematic guided injection parameters for both IPD and ET. Lower scores indicate a better outcome. Means and standard deviations are provided in the data tables. FTM minimum and maximum scores range from 0 to 92 FTM points. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kinematic Tremor Severity | 96 weeks | For two subgroups of participants: (A) those with a \> 8 point improvement on the tremor rating scale and (B) those with a change ≤ 8 points on the tremor rating scale, Group A will have 50% reduction in overall tremor amplitude as measured by kinematics. Kinematic measures were graphically represented as mean angular RMS amplitude and standard deviations of the population at the wrist over three trials during scripted task. Kinematic tremor analysis is shown in angular root mean square (RMS) amplitudes |
Participant flow
Pre-assignment details
Protocol enrollment identifies participants who agreed to participate and sign the consent form (total N=54). However, in the total started participant flow, two participants did not have a high enough tremor severity or consistent tremor severity during the scripted tasks held during the kinematic technology assessment, leaving N=52 in the study
Participants by arm
| Arm | Count |
|---|---|
| Essential Tremor Treatment IncobotulinumtoxinA: A serotype of botulinum toxins that has specificity for cleavage of SYNAPTOSOMAL-ASSOCIATED PROTEIN 25 (SNAP-25). BoNT-A's pharmacological action is to inhibit the release of acetylcholine from the neuromuscular junction. BoNT-A peripherally applied using optimal parameters by intramuscular injections to treat tremor in the most bothersome upper extremity every 16 weeks over 96 weeks. The study will be extended for those participants who benefited and will receive treatment every 12 weeks over 96 weeks. BoNT-A dose will range from 50-300 U per arm. | 24 |
| Parkinson Disease Tremor Treatment IncobotulinumtoxinA: A serotype of botulinum toxins that has specificity for cleavage of SYNAPTOSOMAL-ASSOCIATED PROTEIN 25 (SNAP-25). BoNT-A's pharmacological action is to inhibit the release of acetylcholine from the neuromuscular junction. BoNT-A peripherally applied using optimal parameters by intramuscular injections to treat tremor in the most bothersome upper extremity every 16 weeks over 96 weeks. The study will be extended for those participants who benefited and will receive treatment every 12 weeks over 96 weeks. BoNT-A dose will range from 50-300 U per arm. | 28 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Bothersome hand weakness | 2 | 4 |
| Overall Study | Lack of Efficacy | 2 | 3 |
| Overall Study | Physician Decision | 1 | 4 |
| Overall Study | Protocol Violation | 3 | 3 |
Baseline characteristics
| Characteristic | Essential Tremor Treatment | Parkinson Disease Tremor Treatment | Total |
|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 8.9 | 65 years STANDARD_DEVIATION 11.5 | 68 years STANDARD_DEVIATION 11 |
| Number of participants receiving injection in their motor-dominant limb | 16 Participants | 27 Participants | 43 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Canada | 24 participants | 28 participants | 52 participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Male | 13 Participants | 21 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 28 |
| other Total, other adverse events | 0 / 24 | 0 / 28 |
| serious Total, serious adverse events | 0 / 24 | 0 / 28 |
Outcome results
Primary
Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale)
Improvement in hand tremor as determined by a reduction of \>8 points on a standardized clinical assessment tool (Fahn-Tolosa-Marin Tremor Assessment Scale) pre and post Xeomin® injection using kinematic guided injection parameters for both IPD and ET. Lower scores indicate a better outcome. Means and standard deviations are provided in the data tables. FTM minimum and maximum scores range from 0 to 92 FTM points.
Time frame: 0 to 96 weeks
Population: Mean total FTM score was compared from baseline to each time-point. Here we state the baseline and final visit scores per group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Essential Tremor Treatment | Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale) | Week 0 | 30.6 scores on total FTM scale | Standard Deviation 5.5 |
| Essential Tremor Treatment | Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale) | Week 96 | 14.9 scores on total FTM scale | Standard Deviation 3.5 |
| Parkinson Disease Tremor Treatment | Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale) | Week 0 | 19.4 scores on total FTM scale | Standard Deviation 2.7 |
| Parkinson Disease Tremor Treatment | Clinical Tremor Rating Scale (Fahn-Tolosa-Marin Tremor Rating Scale) | Week 96 | 14.1 scores on total FTM scale | Standard Deviation 3.4 |
p-value: <0.05Linear mixed effects model
Secondary
Kinematic Tremor Severity
For two subgroups of participants: (A) those with a \> 8 point improvement on the tremor rating scale and (B) those with a change ≤ 8 points on the tremor rating scale, Group A will have 50% reduction in overall tremor amplitude as measured by kinematics. Kinematic measures were graphically represented as mean angular RMS amplitude and standard deviations of the population at the wrist over three trials during scripted task. Kinematic tremor analysis is shown in angular root mean square (RMS) amplitudes
Time frame: 96 weeks
Population: Mean kinematic tremor amplitude was compared from baseline to each time-point. Here we state the baseline and final visit tremor amplitudes per group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Essential Tremor Treatment | Kinematic Tremor Severity | Week 0 | 0.73 Angular root mean square amplitude | Standard Deviation 0.69 |
| Essential Tremor Treatment | Kinematic Tremor Severity | Week 96 | 0.15 Angular root mean square amplitude | Standard Deviation 0.26 |
| Parkinson Disease Tremor Treatment | Kinematic Tremor Severity | Week 0 | 1.04 Angular root mean square amplitude | Standard Deviation 0.27 |
| Parkinson Disease Tremor Treatment | Kinematic Tremor Severity | Week 96 | 0.33 Angular root mean square amplitude | Standard Deviation 0.11 |
p-value: <0.05Linear mixed effects model