Boosting Exercise cApaCity With autOnomic Neuromodulation
Condition: Aging; Inflammation; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases; Inflammation
Study type: Interventional

Summary: 
      Background: Exercise performance is a key predictor for healthy ageing. Laboratory and
      clinical data have shown strength of a nerve called the vagus nerve, which is lost during
      age-related disease processes, determines exercise performance. The investigators describe a
      study protocol designed to test the hypothesis that stimulation of the ear (where the vagus
      nerve can be safely stimulated) may improve exercise performance alongside beneficial changes
      in vagus nerve activity in human volunteers.

      Methods. 28 healthy participants aged 18-75y will be randomly allocated to electrical ear
      stimulation or placebo treatment for 30 minutes at the same time of day, for 7 consecutive
      days. Heart monitoring, exercise bike testing, a simple sit-to-stand test and blood sampling
      will be performed immediately before the first day's intervention and after the last day's
      intervention. Participants and investigators will be masked to the treatment allocations and
      analyses. After a 14-day break, participants will perform the same protocol for the opposite
      intervention to their first treatment allocation. The primary outcome will be the change in
      VO2Peak (the best measure of exercise performance) following stimulation or placebo protocol.
      Secondary outcomes include reduction in heart rate after ending the exercise bike test,
      reduction from peak heart rate after standing from sitting, beat-to-beat heart rate measures
      and blood inflammatory marker levels. These outcomes will measure exercise performance and
      vagus nerve function. Safety and complications of the intervention will also be recorded. The
      study was approved by the NHS Research Ethics Committee (21/LO/0856).

      Discussion. This 'first-in-man' study will explore whether non-invasive vagus nerve
      stimulation safely boosts exercise performance and/or vagus nerve activity using electrical
      ear stimulation, providing data for a device-based approach that may be broadly generalisable
      to improving health outcomes.
    

Detailed description: 
      Background A cardinal feature of acute tissue injury/systemic inflammation is the development
      of autonomic dysfunction, characterised by sustained sympathetic hyperactivity and loss of
      vagal function. Elevated resting heart rate is repeatedly associated with both cardiovascular
      morbidity and all-cause mortality in the general population. Vagal tone, which declines
      variably during ageing processes, is the chief determinant of resting heart rate. Healthy
      ageing is characterised by lower sympathetic and preserved vagal activity, reflected by lower
      resting heart rate. The gold-standard measure of vagal tone is heart rate recovery (HRR),
      obtainable from exercise testing. Loss of vagal tone in humans - as quantified by HRR - is
      associated with lower peak aerobic exercise capacity, a major barrier to rehabilitation.
      Persistent sympathetic hyperactivity downregulates G-protein coupled β-receptor recycling.
      This impairs cardiac function, lowers exercise capacity and increases systemic inflammation,
      thereby promoting cardiometabolic disease. Exercise tolerance may be enhanced by dedicated
      exercise training programmes, even in healthy individuals. Greater exercise capacity is
      linked with lower risks of cardiovascular disease, Type 2 diabetes, malignancy, osteoporosis,
      depression and premature death.

      Although in healthy ageing cardiac vagal tone is predominantly determined by genetic factors,
      with strong associations identified between HRR and various genes expressed by key autonomic
      pathway components, vagal neuromodulation techniques have gained traction. Laboratory and
      clinical translational data have shown restoring (or preventing the loss of) vagal activity
      may therefore offer a therapeutic target to help optimise cardiopulmonary fitness and improve
      health outcomes. Stimulation of the dorsal vagal motor nucleus (DVMN) neurones using an
      optogenetic approach increases exercise capacity in rats. In heart failure patents, vagus
      nerve stimulation applied for 15 days was reported to increase the distance of the 6-min walk
      test. Proof-of-concept studies, primarily in human volunteers, using non-invasive electrical
      stimulation of either the auricular branch or the cervical bundle of the vagus nerve suggest
      that maintenance, or augmentation, of vagal activity is feasible, effective and associated
      with minimal side effects. Although transcutaneous stimulation of auricular nerves is readily
      accessible, studies lack focus on autonomic activation and have yet to examine effects on
      exercise capacity.

      Here, the investigators describe the protocol for a randomised controlled crossover trial,
      hypothesizing that bilateral transauricular nerve stimulation (TAN) augments exercise
      capacity in human volunteers. Furthermore, the investigators aim to identify whether TAN
      augments exercise capacity in tandem with autonomic changes that are mechanistically
      implicated in favourably modulating cardiopulmonary fitness.

      Recruitment/screening Potential participants (including NHS patients with no specific
      disease) will be found through posters displayed on NHS premises. After potential
      participants contact the research team, two independent members of the research team at the
      clinical research facility shall be involved - one will obtain informed consent while the
      other will deliver the interventional protocol. The member obtaining consent will call the
      potential participant and screen them against the eligibility criteria before asking for
      consent. All eligible participants that undergo screening will be recorded on a screening log
      on the Investigator Site File, even if they decline the study. Participants will be given a
      participant information sheet (PIS) one week in advance of the first day of intervention.
      Written informed consent must be obtained before the first intervention.

      Informed consent The principal investigator or suitably qualified nominee will obtain written
      informed consent from each participant, including provision of a PIS accompanied by the
      relevant consent form, and an explanation of the aims, methods, anticipated benefits and
      potential hazards of the trial. All potential participants are free to refuse to enter the
      trial or to withdraw at any time during the trial, for any reason. If new safety information
      results in significant changes in the risk/benefit assessment, the PIS and consent form will
      be reviewed and/or amended accordingly. Participants will be informed that, as defined by the
      UK Policy Framework for Health and Social Care Research, all documentation will be stored for
      a minimum of 20 years at the end of the study.

      Sample size Consensus CPET guidelines recommend that the VO2peak should be used to assess
      exercise capacity. The investigators require 28 participants [alpha=0.05; 1-beta=0.9], based
      on the experimental intervention increasing VO2peak (from each individual's own baseline) by
      the same degree as high intensity exercise training (which increases VO2peak by 0.51 l·min-1;
      95% ci: 0.43 to 0.60 l min-1, SD 0.9). The sample size allows for a dropout rate of 10% per
      group.

      Randomisation Participants are randomly assigned (1:1) by block randomisation to receive
      active or sham stimulation first to ensure a balance in sample size across groups over time
      (Power Analysis & Sample Size (PASS) 2021, Utah, USA). Randomisation is performed one week
      before the first intervention, with a random block size of four. A randomisation sequence is
      created by a biostatistician who did not participate in the implementation or statistical
      analysis of trial. Allocation concealment is achieved through sequentially numbered, opaque,
      sealed envelopes.

      Bias/blinding Participants and investigators are blinded to treatment allocations throughout
      data collection and analysis. Participants and investigators are unable to see the device
      settings. Participants are instructed by the investigators that the stimulation is
      imperceptible after determination of the prescription dose. Participants and investigators
      are also masked to the Holter data, which will be analysed offline by an independent trial
      statistician not involved with patient recruitment/device application who is masked to the
      treatment allocations. Interventions are performed at the same time of day to minimise the
      possible influence of circadian variations.

      Data collection Clinical data will be recorded. CPET data will be extracted from the cycle
      ergometer software (Zan, nSpire). Heart rate data will be analysed using Kubios HRV Premium
      [version 3.5.0]. Plasma will be stored at -80ºC having been obtained after both intervention
      periods for exploratory analyses of biomarkers related to autonomic activation. These data
      will be collected by a member of the research team not involved with administering the
      interventions, and analysed by an independent member of the research team - both will be
      masked to the treatment allocations. Data will be entered electronically on a secure database
      (REDCAP).

      Statistical analysis Analyses will be conducted using the intention-to-treat principle, where
      all participants with a recorded outcome are analysed according to the treatment group to
      which they were randomised. Baseline participant characteristics will be presented and
      stratified according to treatment allocation. The primary outcome (absolute change in
      VO2peak) will be analysed using repeat-measures analysis of variance (intervention allocation
      x intervention period) (before versus after TAN/sham). For secondary outcomes, heart rate,
      CPET, HRV data and plasma acetylcholine levels will be compared in each group using
      repeat-measures analysis of variance. Sensitivity analysis for variables that may affect
      exercise capacity and/or autonomic measures will also be conducted. The significance level
      will be set at 0.05. A full statistical analysis plan will be developed prior to analysis and
      the end of the study.

      Trial management/data monitoring The Sponsor organisation is Queen Mary University of London
      (QMUL). Daily trial management will be coordinated by a trial management group consisting of
      the Chief Investigator and his/her support staff. An independent study committee will oversee
      the trial, including assessing the safety of the intervention, reviewing relevant new
      external evidence, and monitoring the overall conduct of the trial. This committee consists
      of an independent clinical trialist, lay representative and an independent Chair.

      Adverse events Prespecified and any other adverse events directly related to the trial
      intervention will be recorded.

      Confidentiality Information related to participants will be kept confidential and managed in
      accordance with the Data Protection Act (UK), NHS Caldecott Principles (UK), the Research
      Governance Framework for Health and Social Care (UK), and the conditions of Research Ethics
      Committee Approval, or corresponding legislation or approvals for a particular participating
      country or site. The principal investigator will maintain in strict confidence trial
      documents (e.g. written consent forms) and confidentiality.

      Discussion Exercise capacity serves as an excellent preoperative prognosticator of an
      individual's ability to cope with the physiological (and pathophysiological) processes
      underlying ageing. Experimental animal studies and human exercise performance data have shown
      intact vagal tone enhances exercise capacity. However, acute tissue injury and systemic
      inflammation disrupt autonomic control. This proof-of-concept study aims to demonstrate the
      safety, feasibility and efficacy of TAN in augmenting cardiopulmonary fitness in tandem with
      autonomic changes that are mechanistically associated with favourable modulation of exercise
      capacity. These healthy volunteer data may offer key insights into potentially accelerating
      functional rehabilitation.

      Experimental data indicate that cardiac vagal activity is a direct determinant of exercise
      capacity. Persistent autonomic dysfunction directly impairs cardiopulmonary fitness and
      therefore muscle mass and strength; key determinants of functional recovery cannot be
      increased. Furthermore, disruption of autonomic-mediated immunoregulatory mechanisms promotes
      a pro-inflammatory state whereby mechanisms controlling the resolution of inflammation are
      suppressed. The development and persistence of autonomic dysfunction therefore directly
      impairs cardiopulmonary fitness and rehabilitation. Therefore, individuals at high risk of
      morbidity and mortality are characterized by reduced vagal tone and slow heart rate recovery
      following incremental exercise.

      Studies of non-invasive autonomic neuromodulation conducted in healthy volunteers and are
      susceptible to bias. The investigators utilised a double-blind, open crossover. randomised
      controlled design to address these issues. Although participants have varying fitness levels
      before the study, each individual serves as their own control. The use of a designated sham
      stimulation device is critical to minimise participant and investigator biases. Far more
      invasive studies have successfully recruited patients into trials where sham procedures
      served as the key control in cardiac and noncardiac orthopaedic surgery.

      Assessing the effects of TAN on exercise capacity in healthy volunteers is broadly
      generalisable to the general population. Provided that the investigators can confirm in this
      setting that autonomic changes after TAN occur by measuring HRV, the low cost, non-invasive
      device used suggests a very low potential risk-to-benefit ratio. Systematic review identified
      TAN stimulation parameters that alter HRV, although there is no certainty that there may be
      minimum thresholds for the duration and/or intensity required to be clinically effective.
      Nonetheless, a 30-minute period of daily tragal stimulation has not been associated with any
      major adverse events.
    

Intervention name(s): Active Transauricular nerve stimulation; Sham transauricular nerve stimulation
Intervention type(s): Device; Device
Intervention description(s): The first allocated intervention will be undertaken for 30 minutes. The electrode placement and stimulation parameters are described in the arm/group section. After the 30-minute intervention, day 1 of the protocol will be complete. The investigator will remain present in the room with the participant to ensure compliance and adherence to the protocol. The allocated intervention will then be repeated by the participant at a similar time of day for 7 consecutive days. The investigator will arrange video-calls with the participant whilst off-site to ensure ongoing compliance and adherence to the protocol. On the seventh day, participants return to the clinical research facility to take the final first allocated intervention. A 14-day rest period will follow. Then the participants will perform the same 7-day protocol for the opposite intervention to their first treatment allocation.; Protocol as for active but sham ear leads are applied, unable to deliver current.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Double-blind, open crossover, randomised sham-controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Neuromodulation; Exercise Training