Patient disposition
Table of Contents
Following approval by the institutional review board (Advarra centrally and three local boards), a total of 405 patients diagnosed with RA were screened for study participation, 243 were consented and enrolled, and 242 completed standard b/tsDMARD washout per protocol requirements before device implantation (intent-to-treat (ITT) population). Figure 1 provides patient disposition from screening through 12 months. Patients were randomized to either arm 1 (stimulation treatment for 3 months, then continued to open-label stimulation; 122 patients) or arm 2 (sham treatment for 3 months, then crossover to open-label stimulation; 120 patients) following postsurgical recovery. One consented patient was discontinued from the study before device implantation for logistical reasons; the patient was not randomized but was followed for safety per protocol. A single patient randomized to arm 1 did not continue in the study after the 3-month primary end point. The demographics and clinical characteristics of the patients at baseline are presented in Table 1 and Supplementary tables 1-3. meen duration of RA was 12.4 years, and the mean (s.d.) and median (range) number of prior b/tsDMARDs was 2.6 (1.9) and 2.0 (1-12), respectively. The total number of patients (% overall population) who had prior exposure to 1 b/tsDMARD was 94 (38.8%), those exposed to >1 b/tsDMARDs was 148 (61.2%),those exposed to ≥3 b/tsDMARDs were 95 (39.3%) and to a tsDMARD were 49 (20.2%). At the time of consent, 78.5% of patients were taking stable doses of a single csDMARD, of which 51.1% were receiving methotrexate. The remainder received at least two csDMARDs. Open-label data are reported through 12 months; 233 patients from the ITT population completed the 12-month visit.
Fig. 1: CONSORT diagram.
Patient disposition through month 12. BMI,body mass index; CVA,cerebrovascular accident; TIA,transient ischemic attack; JAKi,Janus kinaseinhibitor,NSAID,nonsteroidal anti
Study Design and Outcomes in Vagus Nerve Stimulation for Rheumatoid Arthritis
This study investigated the efficacy of vagus nerve stimulation (VNS) in patients with rheumatoid arthritis (RA). Participants were randomized into two arms: one receiving active VNS and the other receiving sham stimulation. The active stimulation intensity was adjusted to a comfortable upper limit (maximum 2.5 mA) and delivered as a 1-minute pulse train at 10 Hz daily. The average stimulation intensity in the active arm was 1.8 mA, while the sham arm received 0 mA.
Assessments were completed for a high percentage of patients (99.2%) at the 3-month mark, with minimal missed visits. The use of ‘rescue’ medications prohibited by the protocol before the 3-month assessment was infrequent, occurring in four patients in the active stimulation arm and five in the sham arm. Blinding was maintained throughout the study,with all involved parties unaware of group assignments until the completion of the 3-month assessments and database lock for primary efficacy analysis.
Following the initial 3-month assessment, all patients were offered the prospect to continue with open-label active VNS. The use of adjunctive pharmacological treatments (‘augmented therapy’) was permitted at the discretion of the rheumatologist, increasing over time from 17.8% at 6 months to 32.2% at 12 months. However, a substantial proportion of patients remained free from traditional b/tsDMARD therapy at these timepoints (88.0%, 80.6%, and 75.2% respectively). A high percentage of patients (96.3%) completed the 12-month assessments within the intent-to-treat (ITT) population.
The primary endpoint of the study was the proportion of patients achieving an ACR20 response at 3 months, compared between the stimulation and sham groups. An ACR20 response is defined as a 20% improvement in both tender and swollen joint counts (out of 28 joints), alongside improvement in at least 3 out of 5 additional measures: HAQ-DI score, patient global assessment, patient pain, evaluator’s global assessment, and high-sensitivity C-reactive protein concentration.
secondary outcomes
four key secondary end points were evaluated, each representing the difference in the proportion of patients in the ITT population receiving stimulation versus sham who achieved the end point at 3 months. End points included a DAS28-CRP good/moderate response according to the European League Against Rheumatism (EULAR) criteria; a DAS28-CRP minimal clinically important difference (MCID; −1.2); a HAQ-DI MCID (−0.22); and an ACR20 response from day 0 (randomization). Among the key secondary end points, multiplicity adjustment was performed using Hochberg’s step-up procedure. all secondary end points showed a higher response rate for stimulation compared to sham, although importance was achieved for only EULAR good/moderate response (Supplementary Table 5).EULAR good/moderate response was achieved by 60.7% of arm 1 (stimulation) and by 41.7% of arm 2 (sham) (multiplicity-adjusted P* = 0.0048, 95% CI = 7.3, 31.7). DAS28-CRP MCID was achieved by 45.1% of arm 1 and by 32.5% of arm 2 (multiplicity-adjusted *P = 0.0528, 95% CI = 1.1, 25.3). HAQ-DI MCID was achieved by 45.9% of arm 1 and by 36.7% of arm 2 (multiplicity-adjusted P* = 0.0797, 95% CI = −3.3, 21.4). ACR20 from day 0 was achieved by 31.1% of arm 1 and by 22.5% of arm 2 (multiplicity-adjusted *P = 0.0797, 95% CI = 1.1, 25.3).
Exploratory outcomes
All other efficacy end points at 3 months and within the open-label stimulation period were exploratory. Open-label stimulation was initiated in both arms after the 3-month controlled-blind period. Response rates for primary and all secondary end points incre
#### Outcome Measures in Rheumatology RA MRI score
Treatment effects on joint inflammation and erosions were assessed using gadolinium-enhanced MRI of the hand and wrist at baseline (pre-implant),3 months and 6 months. Images were analyzed with the validated Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) to objectively quantify bone erosion progression18. In the ITT population,a total of 216 patients had RAMRIS scores measured at both baseline and 3 months (arm 1,*n* = 109; arm 2,*n* = 107). At baseline, bone erosion scores were comparable between arm 1 and arm 2, with a mean (s.d.) erosion score of 10.4 (11.7) and 9.5 (12.1),respectively. from baseline to 3 months, a smaller proportion of patients in arm 1 (stimulation) exhibited progression of bone erosions (>0.5 increase in score) in the evaluated hand and wrist compared with arm 2, although the difference was not significant (*P* = 0.248; Fig. 4c,g). In the prespecified subgroup analysis of patients with a phenotype enriched for erosive damage risk (defined as synovitis score of 2 or more on any individual joint, at least four joints with a score of 1 or any joint with osteitis at baseline), a total of 105 patients met the erosive phenotype criteria (arm 1, *n* = 57; arm 2, *n* = 48). In this subgroup, the rate of progression of bone erosion from baseline to 3 months was considerably decreased in arm 1 (stimulation = 18.9%) as compared with arm 2 (sham = 37.8%, *P* = 0.016; fig. 4e, H).During the open-label stimulation period from 3 months to 6 months, the rate of progression of bone erosion declined in arm 2 (fig. 4g,h).
Efficacy
At 6 months, ACR20 response rates were 50.0% (60/120) in arm 1 and 48.3% (58/120) in arm 2. EULAR good/moderate response was observed in 68.3% (82/120) and 66.7% (80/120) of patients in arm 1 and arm 2, respectively. The proportion of patients achieving DAS28-CRP MCID was 58.3% (70/120) and 54.2% (65/120), while HAQ-DI MCID was achieved by 52.5% (63/120) and 48.3% (58/120) in arm 1 and arm 2, respectively.These results were maintained through 12 months, despite a higher rate of missing data due to missed visits or study dropouts (Supplementary Table 5). At 12 months from baseline, ACR20 response by nonresponder imputation were 50.4% (61/121) and 51.7% (62/120) for arm 1 and arm 2, respectively; EULAR good/moderate response was 70.2% (85/121) and 70.8% (85/120) for arm 1 and arm 2, respectively; DAS28-CRP MCID was 60.3% (73/121) and 55.8% (67/120) for arm 1 and arm 2, respectively; and HAQ-DI MCID was 54.5% (66/121) and 55.8% (67/120) for arm 1 and arm 2, respectively.
Safety
The safety evaluation was based on all available data at the time of reporting, with a mean implant duration of over 700 days. No deaths or unexpected adverse device effects occurred during the trial. Adverse events happened in a similar number of patients in both groups during the controlled period (Table 2 and Supplementary Table 11). Most non-serious related adverse events were linked to the implantation procedure (Supplementary Table 13), reported in 38 patients (15.6%; 52 events). These were similar to what’s been seen with other devices implanted near the cervical vagus nerve. The most common events were mild to moderate hoarseness, categorized as either vocal cord paresis (4.5%,n = 11) or dysphonia (2.9%, n = 7). These adverse events got better over up to a year; three patients received bulk injection.
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