Figure 1
Recruitment Kit and TAPS Device Components. (A) Custom Recruitment Box tailored to ET patients included: Journal, Cala Trio supplied wrist measurement tool, Study Invitation including QR code directing to custom eConsent site, custom personal invitation code. (B) The Cala Trio™ device is comprised of a band, stimulator, and base station. The band is a wristband with embedded electrodes for delivering TAPS to the median and radial nerves. The stimulator snaps into the band to deliver an individualized stimulation pattern to the median and radial nerves. The base station charges the device and uploads device data to a secure cloud platform.
Figure 2
Enrollment flow chart. Of the 310 participants enrolled, 276 completed the one-month study and were included in the modified intention-to-treat (mITT) analysis. Within the mITT population, 242 participants were adequately adherent to protocol and were included in the per-protocol (PP) analysis.
Table 1
Baseline sociodemographic and clinical characteristics of the mITT population.
| CHARACTERISTICS | TOTAL | TX | SOC | p VALUE |
|---|---|---|---|---|
| (N = 276) | (N = 133) | (N = 143) | TX VS SOC | |
| Sociodemographic characteristics | ||||
| Age (years), Mean (SD) | 68.21 (11.09) | 67.77 (11.71) | 68.61 (10.51) | 0.21 |
| Age Group (years), N (%) | 0.62 | |||
| 22–44 | 11 (3.99) | 7 (5.26) | 4 (2.80) | |
| 45–64 | 60 (21.74) | 31 (23.31) | 29 (20.28) | |
| 65–74 | 124 (44.93) | 56 (42.11) | 68 (47.55) | |
| ≥75 | 81 (29.35) | 39 (29.32) | 42 (29.37) | |
| Gender, N (%) | 0.31 | |||
| Male | 183 (66.30) | 84 (63.16) | 99 (69.23) | |
| Female | 93 (33.70) | 49 (36.84) | 44 (30.77) | |
| Race, N (%) | 0.31 | |||
| Black | 5 (1.81) | 1 (0.75) | 4 (2.80) | |
| White | 233 (84.42) | 115 (86.47) | 118 (82.52) | |
| Hispanic | 3 (1.09) | 1 (0.75) | 2 (1.40) | |
| Asian | 3 (1.09) | 3 (2.26) | 0 | |
| More than one race | 3 (1.09) | 2 (1.50) | 1 (0.70) | |
| Other | 4 (1.45) | 1 (0.75) | 3 (2.10) | |
| Unknown | 25 (9.06) | 10 (7.52) | 15 (10.49) | |
| Payers, N (%) | 0.37 | |||
| Commercial insurance | 88 (31.88) | 46 (34.59) | 42 (29.37) | |
| Medicare Advantage | 188 (68.12) | 87 (65.41) | 101 (70.63) | |
| Clinical characteristics | ||||
| Comorbidities | ||||
| Charlson Comorbidity Index (CCI), Mean (SD) | 2.23 (2.50) | 2.06 (2.54) | 2.38 (2.46) | 0.73 |
| Age-adjusted CCI, Mean (SD) | 4.78 (2.94) | 4.58 (3.00) | 4.96 (2.87) | 0.62 |
| Number of comorbidities | 0.99 | |||
| Mean (SD) | 7.20 (3.48) | 7.26 (3.56) | 7.15 (3.42) | |
| Median (IQR) | 7 (5–9) | 7 (4–9) | 7 (5–9) | |
| Psychiatric conditions, N (%) | ||||
| Anxiety | 87 (31.52) | 40 (30.08) | 47 (32.87) | 0.62 |
| Depression | 69 (25.00) | 34 (25.56) | 35 (24.48) | 0.83 |
| Substance use disorders | 28 (10.14) | 11 (8.27) | 17 (11.89) | 0.32 |
| Stress and adjustment disorders | 20 (7.25) | 9 (6.77) | 11 (7.69) | 0.77 |
| Medication use, N (%) | ||||
| ET medications | ||||
| Primidone | 74 (26.81) | 41 (30.83) | 33 (23.08) | 0.15 |
| Propranolol | 58 (21.01) | 22 (16.54) | 36 (25.17) | 0.10 |
| Topiramate | 23 (8.33) | 10 (7.52) | 13 (9.09) | 0.64 |
| Gabapentin | 41 (14.86) | 20 (15.04) | 21 (14.69) | 0.93 |
| Other beta blockers | 143 (51.81) | 73 (54.89) | 70 (48.93) | 0.32 |
| Other benzodiazepines | 15 (5.43) | 10 (7.52) | 5 (3.50) | 0.19 |
| Alprazolam | 21 (7.61) | 12 (9.02) | 9 (6.29) | 0.50 |
| Clonazepam | 12 (4.35) | 5 (3.76) | 7 (4.90) | 0.77 |
| Any ET related medication | 193 (69.93) | 96 (72.18) | 97 (67.83) | 0.43 |
| Number of ET-related Medications | 0.28 | |||
| None | 83 (30.07) | 37 (27.82) | 46 (32.17) | |
| 1 | 61 (22.10) | 26 (19.55) | 35 (24.48) | |
| 2 | 83 (30.07) | 47 (35.34) | 36 (25.17) | |
| 3 | 39 (14.13) | 20 (15.04) | 19 (13.29) | |
| ≥4 | 10 (3.62) | 3 (2.26) | 7 (4.90) | |
| Tremor Characteristics | ||||
| Baseline BF-ADL severity*, N (%) | ||||
| BF-ADL severity ≥2 | 262 (94.93) | 128 (96.24) | 134 (93.71) | 0.41 |
| BF-ADL severity ≥3 | 224 (81.20) | 112 (84.21) | 112 (78.32) | 0.22 |
| BF-ADL severity = 4 | 75 (27.17) | 34 (25.56) | 41 (28.67) | 0.59 |
[i] * BF-ADL tasks associated with eating, drinking, or writing (i.e., use a spoon to drink soup; hold a cup of tea; pour milk from a bottle; write a letter). Patients were classified as having at least one of these 4 BF-ADL tasks with a score of ≥2, ≥3, or = 4.
** See Supplementary Materials (Table S1) for additional sociodemographic and clinical characteristics.
Figure 3
The study met its primary and secondary endpoints. (A and C) Patients in the TX arm had significantly lower (improved) tremor power than patients in the SOC arm in the mITT (primary endpoint, p < 0.0001) and PP (p < 0.0001) populations. 133 TX and 143 SOC patients were included in the mITT analysis while 119 TX and 123 SOC were included in the PP analysis. (B and D) Patients in the TX arm had significantly greater improvement in BF-ADL scores than SOC in the mITT (secondary endpoint, p = 0.0187) and PP populations (p = 0.0077, paired). 134 of the 276 patients and 114 of the 242 patients completed the BF-ADL ratings at baseline and one month for the mITT and PP populations respectively.
Figure 4
BF-ADL score at baseline and the end of one month. BF-ADL scores at one month were lower (i.e., improved) in the TX arm than the SOC arm (p = 0.0078, unpaired).
Figure 5
Additional analyses of tremor power in the TX arm. (A) Tremor power in the TX arm was significantly lower (improved) at post-stimulation compared to pre-stimulation (p < 0.0001; geometric mean ± geometric standard error). (B) Percentage of patients with different levels of median tremor power reduction over all sessions performed. 109 of 133 patients (82%) in the TX arm had some tremor power improvement, 60 of 133 patients (45%) had greater than 50% tremor power improvement, and 30 of 133 (23%) had greater than 70% tremor power improvement.
Table 2
Severe subgroup analyses of primary and secondary endpoints between TX and SOC arm in the mITT population*
| AGE (YEARS) | |||
|---|---|---|---|
| AGE < 65 | AGE ≥ 65 | ALL AGES | |
| Tremor power geometric mean, N, p-value | TX = 0.022 (N = 30) SOC = 0.082 (N = 25) p = 0.0047 | TX = 0.021 (N = 82) SOC = 0.10 (N = 87) p < 0.0001 | TX = 0.022 (N = 112) SOC = 0.097 (N = 112) p < 0.0001 |
| Improvement in BF-ADL score, N, p-value** | TX Δ = 2.18 (N = 11) SOC Δ = 1.21 (N = 19) p = 0.42 | TX Δ = 2.21 (N = 28) SOC Δ = 0.025 (N = 47) p = 0.0096 | TX Δ = 2.21 (N = 39) SOC Δ = 0.35 (N = 66) p = 0.0079 |
[i] * Severe patients were classified as having at least one of 4 tasks which impacts eating, drinking, or writing BF-ADL task ≥3.
** Includes patients with complete BF-ADL scores from baseline and at one month.
Table 3
TAPS device usage and effectiveness by age group and gender in the TX arm.
| NUMBER OF SUBJECTS | ALL PATIENTS | AGE (YEARS) | GENDER | ||||
|---|---|---|---|---|---|---|---|
| <65 | ≥65 | p VALUE | FEMALE | MALE | p VALUE | ||
| N = 1 33 | N = 38 | N = 95 | N = 49 | N = 84 | |||
| Usage patterns, Mean (SD) | |||||||
| Number of sessions per week | 4.34 (4.12) | 3.03 (2.94) | 4.87 (4.41) | 0.0194 | 4.61 (5.12) | 4.19 (3.43) | 0.5740 |
| Number of days per week with at least one session | 3.00 (2.17) | 2.28 (1.84) | 3.29 (2.23) | 0.0142 | 2.95 (2.26) | 3.03 (2.14) | 0.8416 |
| Number of sessions per day on days when therapy used | 1.32 (0.49) | 1.25 (0.41) | 1.35 (0.52) | 0.3198 | 1.38 (0.68) | 1.29 (0.35) | 0.3446 |
| Tremor power improvement ratio1, Mean (95% CI) | |||||||
| Improvement ratio, all sessions | 3.51 (2.46–4.56) | 4.43 (2.48–6.36) | 3.16 (2.20–4.10) | 0.2841 | 2.98 (1.77–4.20) | 3.81 (2.30–5.32) | 0.4541 |
| Improvement2 in BF-ADL score, Mean (SD) | |||||||
| Improvement in BF-ADL score | 1.59 (3.07) | 1.81 (1.91) | 1.48 (3.50) | 0.0147 | 1.57 (2.27 | 1.59 (3.35) | 0.1355 |
| BF-ADL individual task improvements2 in patients with ≥ 3 at baseline for each task, Mean (SE) | |||||||
| Pour milk from a bottle | 0.92 (0.15) (N = 24, p < 0.0001) | ||||||
| Insert an electric plug | 0.80 (0.21) (N = 20, p = 0.0013) | ||||||
| Hold a cup of tea | 0.73 (0.11) (N = 40, p < 0.0001) | ||||||
| Dial a telephone | 0.70 (0.18) (N = 20, p = 0.0009) | ||||||
| Use a spoon to drink soup | 0.61 (0.11) (N = 46, p < 0.0001) | ||||||
| Unlock front door | 0.50 (0.20) (N = 16, p = 0.0271) | ||||||
| Pick up change | 0.37 (0.19) (N = 19, p = 0.0691) | ||||||
| Write a letter | 0.31 (0.08) (N = 62, p = 0.0006) | ||||||
[i] 1 Device-measured outcome, improvement ratio was defined pre-stimulation tremor power divided post-stimulation tremor power.
2 BF-ADL improvement, BF-ADL score changes defined as BF-ADL score at the end of one month minus BF-ADL score at baseline multiplied by –1. A positive value indicates improved ADL from baseline over one month.