Figure 1
Study design, therapeutic device, and calibration postures. (A) The study included 3 in-clinic visits over 3 months with interim prescribed twice-daily home-use of therapy. (B) The wrist-worn device consisted of a stimulator, detachable band, and base station. The stimulator applied the stimulation pattern to the band and had an onboard triaxial accelerometer to measure tremor. The band contained two working electrodes positioned over the median and radial nerves and a counter-electrode positioned on the dorsal side of the wrist. The base station streamed accelerometer and usage data daily and charged the device. (C) Patients performed either a lateral or forward postural hold for device calibration and for tremor measurement pre- and post-stimulation.
Table 1
Enrolled patient demographics (N = 263).
| Demographics | |
|---|---|
| Female | 52% (137) |
| Age | 69.6 ± 10.1 (23–89) |
| BMI | 28.2 ± 5.4 (16–48) |
| Race | |
| Asian | 4% (11) |
| Black or African American | 3% (7) |
| White | 90% (237) |
| More than one race | 1% (3) |
| Unknown or not reported | 2% (5) |
| Ethnicity | |
| Hispanic or Latino | 3% (7) |
| Not Hispanic or Latino | 96% (253) |
| Unknown or not reported | 1% (3) |
| Clinical Characteristics | |
| Onset Age | 43.9 ± 20.4 (2–79) |
| ET Duration | 25.6 ± 18.1 (1–76) |
| Family History | |
| Yes | 62% (163) |
| No | 27% (71) |
| Don’t Know | 11% (29) |
| On ET Medications | 66% (173) |
| On Antidepressant Medications | 14% (36) |
| Prior ET Treatment (Any) | 78% (206) |
| Prior ET Medications | 78% (205) |
| Prior Botulinum | 4% (11) |
| Responsive to Alcohol | 37% (96) |
[i] Reported as % patients (#) or mean ± SD (min – max).
Table 2
Descriptive statistics of co-primary and secondary endpoints.
| Baseline Mean (SD) | Final visit Mean (SD) | Change Mean (SD) | ||
|---|---|---|---|---|
| Co-primary endpoints1 | ||||
| TETRAS dominant hand score2 | 12.6 (2.7) | 9.8 (3.5) | –2.8 (2.8)* | |
| BF-ADL dominant hand score3 | 18.4 (3.8) | 13.4 (4.4) | –5.0 (4.3)* | |
| Secondary endpoint4 | ||||
| Tremor power (m/s2)2 | 1.1 (4.4) | 0.3 (1.1) | –0.8 (3.7)* | |
[i] * p ≪ 0.0001 after Holm-Bonferroni corrections for multiple hypothesis testing.
1 n = 205; 2 Minimum score 0, maximum score 24; 3 Minimum score 8, maximum score 32; 4 n = 193.
Figure 2
Co-primary endpoints assessed in-clinic showed improvement in TETRAS and BF-ADL. Average TETRAS dominant hand score (left, scale range 0–24) and BF-ADL dominant hand score (right, scale range 8 to 32) are shown pre- and post-stimulation conducted at each in-clinic visit. The co-primary TETRAS and BF-ADL endpoints—improvement from baseline (pre-stimulation rating at Visit 1) to study exit (post-stimulation rating at Visit 3)—were both met (n = 205). Therapeutic response was also significant within each visit for both TETRAS and BF-ADL, and the pre-stimulation tremor rating improved significantly over 3 months of use. Error bars represent ±1 SEM, and * indicates p < 0.0001.
Figure 3
Tremor severity distributions shifted towards milder tremor at study exit. (A) The distribution of tremor severity at the time of co-primary endpoints (i.e., Visit 1 pre-stimulation to Visit 3 post-stimulation) were assessed for TETRAS (left) and BF-ADL (right). On both scales, the distribution of tremor severity shifted towards milder tremor. (B) Study exit (Visit 3 post-stimulation) tremor severity distributions were broken down for each baseline severity group for TETRAS (left) and BF-ADL (right). Most patients improved in tremor severity relative to their baseline or stayed in the same severity classification, with more severe patients showing greater improvement. Severity categories were defined consistent with TETRAS guidelines.
Table 3
Co-primary outcomes by task.
| Patient count per task1 | Baseline Mean (SD) | Final visit Mean (SD) | Change Mean (SD) | % Patients improved2 | ||
|---|---|---|---|---|---|---|
| TETRAS Tasks3 | ||||||
| Forward Outstretched | 124 | 2.2 (0.3) | 1.5 (0.6) | –0.6 (0.6)* | 78% | |
| Lateral | 140 | 2.3 (0.4) | 1.7 (0.7) | –0.6 (0.6)* | 80% | |
| Kinetic | 163 | 2.3 (0.4) | 1.7 (0.6) | –0.6 (0.5)* | 79% | |
| Spiral | 161 | 2.5 (0.7) | 2.0 (0.8) | –0.5 (0.8)* | 58% | |
| Handwriting | 144 | 2.8 (0.7) | 2.0 (1.0) | –0.8 (0.8)* | 67% | |
| Dot Approximation | 155 | 2.4 (0.5) | 1.9 (0.7) | –0.4 (0.6)* | 66% | |
| BF-ADL Tasks4 | ||||||
| Use a spoon to drink soup | 196 | 2.9 (0.6) | 2.0 (0.9) | –0.9 (0.8)* | 70% | |
| Hold a cup of tea | 192 | 2.8 (0.7) | 1.8 (0.9) | –1.0 (0.9)* | 71% | |
| Pour milk from a bottle | 182 | 2.8 (0.7) | 1.8 (0.9) | –1.0 (0.9)* | 69% | |
| Dial a telephone | 131 | 2.6 (0.7) | 1.8 (0.9) | –0.8 (0.8)* | 76% | |
| Pick up change | 134 | 2.6 (0.7) | 1.8 (0.9) | –0.8 (0.8)* | 69% | |
| Insert an electric plug | 134 | 2.4 (0.5) | 1.5 (0.6) | –0.9 (0.8)* | 69% | |
| Unlock front door | 148 | 2.4 (0.5) | 1.5 (0.6) | –0.9 (0.8)* | 72% | |
| Write a letter | 192 | 2.3 (0.5) | 1.5 (0.7) | –0.8 (0.8)* | 61% | |
[i] *p ≪ 0.0001 after Holm-Bonferroni corrections for multiple hypothesis testing.
1 Count of patients scoring at least “Mild” per task (2 on TETRAS or BF-ADL).
2 Defined as % patients improving at least one increment (0.5 or 1, depending on scale and task).
3 Each TETRAS task rated 0–4 by clinician (0 = normal, 1 = slight, 2 = mild, 3 = moderate, 4 = severe).
4 Each BF-ADL task rated 1–4 by patient (1 = without difficulty, 2 = with a little effort, 3 = with a lot of effort, 4 = cannot do by yourself).
Figure 4
Secondary endpoint from at-home accelerometer measures show improvement in tremor physiology with therapy. (A) Average tremor power decreased from pre-stimulation to post-stimulation (data represents 193 patients and 21,806 total sessions). Error bars represent ±1 SEM, and * indicates p < 0.0001. (B) Tremor power, computed from the triaxial acceleration signals, was correlated to the clinician-rated TETRAS postural hold rating (r = 0.67, p < 0.0001). (C) Example 3-second segment of the wrist acceleration time series along one of the three accelerometer axes with corresponding tremor power measures are shown for a single session before and after stimulation. (D) 92% of all patients had an improvement ratio > 1, indicating an improvement in tremor power from pre- to post-stimulation. Each bar represents a single-patient’s median improvement in tremor power from pre- to post-stimulation over all at-home stimulation sessions over three months (n = 193 patients).
Table 4
Device-related adverse events.
| Adverse Event Type1 | % Subjects (#) | # Events |
|---|---|---|
| All | 17.9% (47) | 56 |
| Significant and persistent skin irritation (including redness, itchiness, and/or swelling) | 5.3% (14) | 15 |
| Sore/Lesion | 3.8% (10) | 11 |
| Significant discomfort | 2.3% (6) | 7 |
| Electrical burns | 2.3% (6) | 6 |
| Other: minor skin irritation (including itchiness and/or redness) | 2.3% (6) | 6 |
| Other: electric shock sensation while using device | 1.1% (3) | 3 |
| Other: worsening of tremor | 0.8% (2) | 2 |
| Other isolated events2 | 2.0% (5) | 6 |
[i] 1 Rated by investigator to be possibly, probably or definitely device-related.
2 Each of the following occurred in only one patient: fall, anxiety, intermittent soreness in treated wrist, weakness or lack of coordination in treated hand, persistent pain from stimulation.
Figure 5
Clinical and Patient Global impression of improvement (C/PGI-I). Clinicians and patients were surveyed with the 7-point global impression scale of improvement at Visit 3 post the in-clinic stimulation session to assess improvements in dominant hand tremor relative to baseline. Clinicians (CGI-I) and patients (PGI-I) reported hand tremor minimally, much or very much improved in 68% and 60% of patients, respectively.
| Name | Location | Role | Contribution |
|---|---|---|---|
| Stuart Isaacson, MD | Parkinson’s Disease and Movement Disorders of Boca Raton, Boca Raton | Author | Study design, Principal investigator on the research, manuscript review and critique |
| Elizabeth Peckham, DO | Central Texas Neurology Consultants, Round Rock | Author | Site investigator on the research, manuscript review and critique |
| Winona Tse, MD | Mount Sinai Hospital, New York | Author | Site investigator on the research, manuscript review and critique |
| Olga Waln, MD | Houston Methodist, Houston | Author | Site investigator on the research, manuscript review and critique |
| Christopher Way, DO | Parkinson’s Institute and Clinical Center, Mountain View | Author | Site investigator on the research, manuscript review and critique |
| Melita Petrossian, MD | Pacific Neuroscience Institute, Santa Monica | Author | Site investigator on the research, manuscript review and critique |
| Nabila Dahodwala, MD, MSc | University of Pennsylvania. Philadelphia | Author | Site investigator on the research, manuscript review and critique |
| Michael Soileau, MD | Texas Movement Disorders Specialists, Georgetown | Author | Site investigator on the research, manuscript review and critique |
| Mark Lew, MD | USC, Los Angeles | Author | Site investigator on the research, manuscript review and critique |
| Cameron Dietiker, MD | UCSF, San Francisco | Author | Site investigator on the research, manuscript review and critique |
| Nijee Luthra, MD | UCSF, San Francisco | Author | Site investigator on the research, manuscript review and critique |
| Pinky Agarwal, MD, FAAN | EvergreenHealth, Kirkland | Author | Site investigator on the research, manuscript review and critique |
| Rohit Dhall, MD, MSPH | UAMS, Little Rock | Author | Site investigator on the research, manuscript review and critique |
| John Morgan, MD, PhD | Augusta University, Augusta | Author | Site investigator on the research, manuscript review and critique |
| Nicole Calakos, MD, PhD | Duke University, Durham | Author | Site investigator on the research, manuscript review and critique |
| Theresa Zesiewicz, MD | USF, Tampa | Author | Site investigator on the research, manuscript review and critique |
| Ejaz A. Shamim, MD, MS, MBA, FAAN | Kaiser Permanente, MidAtlantic States, MidAtlantic Permanente Research Institute | Author | Site investigator on the research, manuscript review and critique |
| Rajeev Kumar, MD | Rocky Mountain Movement Disorders Center, Englewood | Author | Site investigator on the research, manuscript review and critique |
| Peter LeWitt, MD | Henry Ford Health System, West Bloomfield | Author | Site investigator on the research, manuscript review and critique |
| Holly Shill, MD, FAAN | Barrow Neurological Institute, Phoenix | Author | Site investigator on the research, manuscript review and critique |
| Adam Simmons, MD | Hospital for Special Care, New Britain | Author | Site investigator on the research, manuscript review and critique |
| Fernando Pagan, MD | Georgetown University, Washington DC | Author | Site investigator on the research, manuscript review and critique |
| Pravin Khemani, MD | Swedish, Seattle | Author | Site investigator on the research, manuscript review and critique |
| Jessica Tate, MD | Wake Forest, Winston-Salem | Author | Site investigator on the research, manuscript review and critique |
| Brian Maddux, MD | Riverhills Neuroscience, Cincinnati | Author | Site investigator on the research, manuscript review and critique |
| Lan Luo, MD, MS | Beth Israel Deaconess Medical Center, Boston | Author | Site investigator on the research, manuscript review and critique |
| William Ondo, MD | Houston Methodist, Houston | Author | Device Safety Monitoring Board; manuscript review and critique |
| Mark Hallett, MD | NIH, Bethesda | Author | Study design, manuscript review and critique. No clinical work was done at NIH. |
| Apoorva Rajagopal, PhD | Cala Health, Burlingame | Author | Manuscript drafting, review and critique |
| Paula Chidester, MS | Cala Health, Burlingame | Author | Study design, manuscript drafting, review and critique |
| Kathryn Rosenbluth, PhD | Cala Health, Burlingame | Author | Study design, manuscript drafting, review and critique |
| Scott Delp, PhD | Stanford University, Stanford | Author | Study design, manuscript drafting, review and critique |
| Rajesh Pahwa, MD | University of Kansas Medical Center, Kansas City | Author | Study design, Principal investigator on the research, manuscript review and critique |