Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial 2025 Tesser et al

J

Jaybee00

Senior Member (Voting Rights)

Abstract​

The inflammatory reflex, in which vagus nerve signaling modulates cytokine production, is dysregulated in rheumatoid arthritis (RA). RESET-RA, a pivotal, double-blind, randomized, sham-controlled trial, evaluated a vagus nerve-targeted neuromodulation system for RA in 242 patients with inadequate response/intolerance to biological/targeted synthetic disease-modifying antirheumatic drugs. Patients were randomized to active or sham stimulation for 3 months, and then all received open-label stimulation with results reported to 12 months. The primary end point was 3-month American College of Rheumatology 20% (ACR20) response. ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209), which further improved in open-label to 50.0% at 6 months and 52.8% at 12 months (all-completers). Adverse events occurred in a similar proportion of patients in both arms. Related serious adverse events (rate = 1.6%) were all perioperative, and resolved. Vagus nerve-mediated neuroimmune modulation for RA achieved its primary efficacy end point and produced durable clinical benefits with a favorable safety profile. ClinicalTrials.gov registration: NCT04539964.

 
Fig. 2: Integrated neuromodulation system.
figure 2
The integrated neuromodulation system consists of an implant and pod. The implant is placed in the pod to position and hold it in place on the left cervical vagus nerve to ensure direct contact for precise stimulation. The implant is approximately 2.5 cm in length and weighs 2.6 g. To charge the implant, patients wear a wireless device (charger) around the neck for a few minutes, once a week. The implant is programmed by healthcare providers (HCPs) using a proprietary application (programmer).
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It was not much stimulation, only 1 minute daily:
The active stimulation intensity was set to an upper comfort level (maximum = 2.5 mA) and delivered a 1-min train of pulses to the vagus nerve once daily at 10 Hz16 (arm 1 = 1.8 mA average; arm 2 = 0 mA).
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They were allowed to use other treatments after the 3 month blind period:
Following the primary end point assessment at 3 months, all patients were eligible to continue in the study for open-label active stimulation treatment. Adjunctive pharmacological treatments (‘augmented therapy’) were permitted throughout the open-label stimulation period at the discretion of the rheumatologist in consultation with the patient, with 17.8%, 24.8% and 32.2% of patients receiving protocol-defined augmented therapy at 6, 9 and 12 months, respectively. At these timepoints, 88.0%, 80.6% and 75.2% of patients remained free from adjunctive b/tsDMARD therapy.
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They used Bang’s blinding index to assess blinding. I’m not very familiar with the index, but a visual inspection of the data shows what I believe is a clear skew towards guessing correctly in both groups:
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Utsikt said:
They used Bang’s blinding index to assess blinding. I’m not very familiar with the index, but a visual inspection of the data shows what I believe is a clear skew towards guessing correctly in both groups:
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This is good to see. I’m suprised the authors wrote “pivotal” in their title after this data + the open label data seems to clearly indicate that this trial is not enough to make out an effect or not.
 
Utsikt said:
At this point I’ve stopped being surprised at the dishonesty in science.. Everything is propaganda unless proven otherwise.
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Yes my “surprise” was rhetorical. A hedged and euphemised way to say that the authors seem to come to a conclusion explicitly not supported by their evidence.

Unfortunately outside this community I have to find ways to hedge and soften down my critiques because everyone seems to take being published in a paper as gospel. (I imagine if I had the energy of a healthy person I could be more outspoken but I never really have the energy to debate so I try not to provoke them ahah).
 
Yann04 said:
Yes my “surprise” was rhetorical. A hedged and euphemised way to say that the authors seem to come to a conclusion explicitly not supported by their evidence.

Unfortunately outside this community I have to find ways to hedge and soften down my critiques because everyone seems to take being published in a paper as gospel. (I imagine if I had the energy of a healthy person I could be more outspoken but I never really have the energy to debate so I try not to provoke them ahah).
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Sounds reasonable. I have the same experience! It’s incredibly frustrating..
 
Utsikt said:
They used Bang’s blinding index to assess blinding. I’m not very familiar with the index
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Assessment of blinding in clinical trials (2004)

Success of blinding is a fundamental issue in many clinical trials. The validity of a trial may be questioned if this important assumption is violated. Although thousands of ostensibly double-blind trials are conducted annually and investigators acknowledge the importance of blinding, attempts to measure the effectiveness of blinding are rarely discussed. Several published papers proposed ways to evaluate the success of blinding, but none of the methods are commonly used or regarded as standard.

This paper investigates a new approach to assess the success of blinding in clinical trials. The blinding index proposed is scaled to an interval of −1 to 1, 1 being complete lack of blinding, 0 being consistent with perfect blinding and −1 indicating opposite guessing which may be related to unblinding. It has the ability to detect a relatively low degree of blinding, response bias and different behaviors in two arms.

The proposed method is applied to a clinical trial of cholesterol-lowering medication in a group of elderly people.

Web | Controlled Clinical Trials | Paywall

A simple blinding index for randomized controlled trials (2024)

Blinding is an essential part of many randomized controlled trials. However, its quality is usually not checked, and when it is, common measures are the James index and/or the Bang index. In the present paper we discuss these two indices, providing examples demonstrating their considerable weaknesses and limitations, and propose an alternative method for measuring blinding. We argue that this new approach has a number of advantages. We also provide an R-package for computing our blinding index.

Web | Contemporary Clinical Trials Communications | Open Access
 
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