Figure 1
CONSORT Flow Diagram Displaying the Progress of the Study Design. Progress through the various stages of a trial including flow of participants, number reasoning of withdrawals and the number of participants included for analysis.
Figure 2
Kinematic Sensor Placement for Tremor Assessment. Placement of biometric motion sensors along the arm: shoulder electrogoniometer, elbow electrogoniometer, wrist electrogoniometer. Accelerometers were placed on the forearm, hand, and third finger.
Figure 3
Standard Scripted Tasks Performed by Each Participant during Kinematic Recording Sessions. (A) Rest position (rest-1) with relaxed forearm in lap measuring flexion–extension (F/E) wrist movements. (B) Rest position (rest-2) with arm supported measuring P/S movements. (C) Posture-1 position with shoulders flexed at 90° with arms extended anteriorly and pronated (palms facing downwards). (D) Posture-2 position with shoulders flexed at 90° with arms extended anteriorly, palms facing inwards.
Table 1
PD Participant Demographics and Baseline UPDRS Scores
| Baseline Scores | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient ID | Gender | Age | Years with Tremor | Injected Limb | Dominant Limb | Weight (lbs) | Item 20 Non-treated Arm (/4) | Item 20 Treated Arm (/4) | Item 21 Non-treated Arm (/4) | Item 21 Treated Arm (/4) |
| 1 | F | 71 | 11 | L | R | 170 | 0 | 2 | 1 | 2 |
| 2 | M | 35 | 7 | R | R | 350 | 0 | 2 | 0 | 3 |
| 3 | M | 62 | 7 | R | R | 175 | 0 | 3 | 0 | 0 |
| 4 | M | 79 | 7 | R | R | 165 | 2 | 3.5 | 1 | 1 |
| 5 | M | 53 | 10 | L | R | 2 | 3 | 1 | 2.5 | |
| 6 | M | 43 | 5 | L | R | 1 | 2 | 1 | 2 | |
| 7 | M | 60 | 7 | R | R | 225 | 1 | 3 | 1 | 2.5 |
| 8 | M | 79 | 14 | R | R | 4 | 4 | 2 | 2 | |
| 9 | M | 59 | 11 | R | R | 275 | 2 | 2 | 1 | 1 |
| 10 | F | 77 | 9 | L | R | 185 | 1 | 3 | 1 | 2 |
| 11 | M | 62 | 5 | R | R | 203 | 2 | 3 | 0 | 0 |
| 12 | M | 66 | 7 | R | R | 185 | 0 | 2.5 | 1 | 1 |
| 13 | M | 76 | 6 | R | R | 152 | 1 | 2 | 0 | 1 |
| 14 | F | 54 | 6 | R | R | 140 | 0 | 2 | 1 | 0 |
| 15 | F | 50 | R | R | 0 | 3 | 0 | 2 | ||
| 16 | F | 75 | R | R | 0 | 3 | 2 | 2 | ||
| 17 | F | 62 | 8 | L | R | 152 | 2 | 3.5 | 1 | 2.5 |
| 18 | F | 47 | 14 | R | R | 193 | 1 | 2 | 1 | 2 |
| 19 | F | 71 | R | R | 0 | 2.5 | 1 | 2 | ||
| 20 | M | 80 | 9 | R | R | 150 | 0 | 3.5 | 0 | 0 |
| 21 | M | 59 | 7 | L | R | 170 | 0 | 3 | 0 | 2 |
| 22 | M | 69 | 6 | R | R | 234 | 0 | 3.5 | 0 | 2.5 |
| 23 | F | 70 | 6 | R | R | 165 | 2 | 2 | 2.5 | 2.5 |
| 24 | M | 68 | 14 | R | R | 160 | 3 | 3 | 1 | 1 |
| 25 | M | 70 | 7 | R | R | 165 | 0 | 3.5 | 0 | 3.5 |
| 26 | M | 69 | L | R | 215 | 0 | 2 | 0 | 1 | |
| 27 | F | 80 | 5 | R | R | 150 | 1 | 2.5 | 1 | 1 |
| 28 | F | 66 | L | R | 168 | 1 | 2.5 | 0 | 1 | |
| Mean | 7F | 65.5 | 7.5 | 8L | 1L | 188.2 | 0.9 | 2.7 | 0.7 | 1.6 |
| ± SD | ± 11.5 | ± 3.1 | ± 47.5 | ± 1.0 | ± 0.6 | ± 0.7 | ± 0.9 | |||
[i] Abbreviations: F, Female; L, Left; M, Male; PD, Parkinson’s Disease; R, Right; SD, Standard Deviation; UPDRS, Unified Parkinson’s Disease Rating Scale.
Figure 4
Sample Participant Kinematic Data Readout of Tremor Generated from the Wrist, Elbow, and Shoulder Joints and Individualized Muscle Selection Based on the Kinematic Tremor Profile and the Injector’s Best Clinical Judgment. (A) Total tremor severity (plot 1) is displayed in angular RMS amplitude and the percentage of directional contribution of tremulous movement (plot 2) by three degrees of freedom in the wrist and by two degrees of freedom in the shoulder joint. Error bars indicate standard deviation over three trials. (B) Injector’s interpretation of the kinematic results showing selection of total dose allocated to wrist, elbow, and shoulder muscle groups based on tremor severity and the muscles selected on the basis of the amount of tremor present in each degree of freedom each arm joint moves in.
Abbreviations: Fl-Ex, flexion-extension; Ra-Ul, radial-ulnar; Pr-Su, pronation-supination; Shl-Flx, shoulder flexion-extension; Shl-Abd, shoulder abduction-adduction.
Table 2
Total Injected Dosage and Number of Muscles Injected as Determined by Injector Across all Participants
| Week 0 (First Injection) | Week 16 (Second Injection) | Week 32 (Third Injection) | ||||
|---|---|---|---|---|---|---|
| Patient | BoNT-A Dose (U) | No. of Muscles Injected | BoNT-A Dose (U) | No. of Muscles Injected | BoNT-A Dose (U) | No. of Muscles Injected |
| 1 | 100 | 6 | No injection1 | 75 | 8 | |
| 2 | 200 | 7 | 200 | 7 | No Injection1 | |
| 3 | 100 | 6 | 100 | 6 | No Injection1 | |
| 4 | 100 | 8 | 200 | 8 | No Injection1 | |
| 5 | 100 | 8 | 100 | 8 | No Injection1 | |
| 6 | 100 | 6 | Withdrawn4 | Withdrawn4 | ||
| 7 | 200 | 8 | No Injection1 | 200 | 8 | |
| 8 | 275 | 8 | Withdrawn4 | Withdrawn4 | ||
| 9 | 260 | 9 | 390 | 11 | No Injection1 | |
| 10 | 125 | 7 | No injection2 | 125 | 7 | |
| 11 | 140 | 8 | 175 | 9 | No injection3 | |
| 12 | 100 | 8 | 170 | 8 | 100 | 8 |
| 13 | 175 | 8 | 175 | 8 | 135 | 8 |
| 14 | 95 | 7 | 95 | 7 | 95 | 7 |
| 15 | 320 | 11 | 350 | 11 | Withdrawn4 | |
| 16 | 200 | 11 | Withdrawn5 | Withdrawn5 | ||
| 17 | 200 | 11 | 280 | 9 | 300 | 8 |
| 18 | 200 | 10 | 200 | 10 | 200 | 10 |
| 19 | 200 | 6 | Withdrawn4 | Withdrawn4 | ||
| 20 | 265 | 13 | 300 | 13 | 300 | 13 |
| 21 | 200 | 8 | 280 | 12 | 300 | 13 |
| 22 | 200 | 8 | 100 | 8 | 100 | 8 |
| 23 | 190 | 11 | 170 | 11 | 170 | 11 |
| 24 | 200 | 8 | 200 | 8 | 200 | 11 |
| 25 | 300 | 12 | 300 | 12 | 300 | 12 |
| 26 | 100 | 7 | 200 | 9 | Withdrawn5 | |
| 27 | 130 | 9 | 200 | 11 | 200 | 11 |
| 28 | 100 | 6 | 80 | 6 | Withdrawn6 | |
| Mean±SD | 174.1±66.8 | 8.4±1.9 | 203.1±84.4 | 9.1±2.0 | 186.7±79.5 | 9.5±2.1 |
Abbreviations: BoNT-A, IncobotulinumtoxinA; SD, Standard Deviation.
Note: Dosing was in BoNT-A units.
1 Participant presented with minimal tremor at visit and injector made a clinical judgment against injection.
Table 3
Mean Injection Dosage by Arm Muscle Treated at Each Treatment Time Point
| Muscles Injected | First Injection (Week 0) | Second Injection (Week 16) | Third Injection (Week 32) | |||
|---|---|---|---|---|---|---|
| Mean±SD | No. of Patients (n=28) | Mean±SD | No. of Patients (n=21) | Mean±SD | No. of Patients (n=15) | |
| Flexor carpi radialis | 16.3±7.0 | 24 | 15.6±5.7 | 17 | 13.6±5.8 | 14 |
| Flexor carpi ulnaris | 16.8±6.7 | 28 | 16.1±5.8 | 19 | 14.2±5.5 | 13 |
| Brachioradialis | 20.0±0.0 | 1 | 20.0±0.0 | 1 | 20.0±0.0 | 1 |
| Extensor carpi radialis | 18.5±8.2 | 24 | 17.5±5.8 | 18 | 16.1±5.4 | 14 |
| Extensor carpi ulnaris | 18.6±7.9 | 28 | 17.5±5.8 | 20 | 16.5±5.3 | 13 |
| Pronator teres | 17.4±5.1 | 25 | 17.8±4.9 | 20 | 15.7±4.2 | 14 |
| Pronator quadratus | 16.0±4.9 | 25 | 17.3±5.1 | 20 | 15.4±4.8 | 14 |
| Supinator | 17.3±4.5 | 22 | 18.1±4.8 | 18 | 16.8±7.0 | 14 |
| Biceps brachii | 33.9±10.3 | 23 | 36.3±10.4 | 19 | 30.4±9.7 | 12 |
| Triceps | 29.5±10.1 | 10 | 32.7±9.6 | 11 | 28.1±9.3 | 8 |
| Pectoralis major | 33.3±8.8 | 9 | 34.5±13.0 | 11 | 28.1±9.3 | 6 |
| Teres major | 25.8±6.7 | 6 | 30.0±12.2 | 8 | 29.2±10.6 | 8 |
| Deltoid | 30.0±9.4 | 4 | 32.0±9.3 | 5 | 30.0±5.5 | 5 |
| Supraspinatus | 28.0±2.4 | 5 | 30.0±5.5 | 5 | 27.5±2.5 | 4 |
[i] Abbreviation: SD, Standard Deviation.
[ii] Note: All the dosages are in units of BoNT-A. The mean values represent the average dose administered in the mean number of participants injected in that particular muscle.
Figure 5
IncobotulinumtoxinA Treatments Significantly Reduced Tremor Severity and Improved Arm Function in the Treated Arm of Parkinson’s Disease Participants Reported Qualitatively and Quantitatively. (A) Unified Parkinson’s Disease Rating Scale item 20 and 21 mean scores (max: four per arm) for rest and action tremor, respectively. (B) Fahn–Tolosa–Marin (FTM) part A score (max: 12 per arm), sum of tremor severity during rest, posture, and action tasks, significantly decreased. FTM part C score (max: four per category), functional disability, was significantly reduced for eating tasks (N=7). (C) Angular RMS tremor amplitude (primary y-axis) and hand and finger accelerometer values (secondary y-axis) for each arm joint were averaged over two rest and two postural tasks per time point. Significant reductions in wrist amplitude and finger accelerometry were observed. (D) Angular wrist tremor RMS amplitude and (E) mean x-y-z tremor acceleration captured from the third finger displayed for each rest and postural task showed significant reduction. (F) Maximal grip strength (blue line) and perceived muscle weakness (red line) yielded significant change at week 22.
Abbreviations: UPDRS, Unified Parkinson's Disease Rating Scale; FTM, Fahn-Tolosa-Marin; RMS, root mean square.
Table 4
Number of Participants Who Perceived Weakness Using a Likert Scale Over the Treatment Course
| Time | Number of Participants Per Likert Score | ||||
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | |
| Week 0 (n=18) | 15 | 3 | – | – | – |
| Week 6 (n=21) | 9 | 6 | 5 | 1 | – |
| Week 16 (n=18) | 11 | 6 | 1 | – | – |
| Week 22 (n=17) | 4 | 8 | 5 | – | – |
| Week 32 (n=19) | 9 | 8 | 2 | – | – |
| Week 38 (n=14) | 4 | 8 | 1 | 1 | – |
[i] Note: Likert scale scores ranged from 0 = no weakness, 1 = mild weakness in non-injected muscles, 2 = mild weakness in injected muscles, 3 = moderate weakness in injected muscles and 4 = severe weakness in injected muscles.