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Post-Treatment Lyme Disease SyndromeRavLymeNCT04938687

Effect of Auricular Vagal Nerve Electrical Stimulation on Post-Treatment Lyme Disease Syndrome

A study testing respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) in people with Post-Treatment Lyme Disease Syndrome, run by Spaulding Rehabilitation Hospital.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study is to assess if respiratory-gated auricular vagal nerve stimulation (RAVANS) can improve symptoms of post-treatment Lyme disease syndrome Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Post-Treatment Lyme Disease Syndrome
What is being tested?
respiratory-gated auricular vagal afferent nerve stimulation (RAVANS)
Type of treatment
Medical device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
15 participants
Where
No sites listed yet
Study dates
31 May 2022to 25 Apr 2025
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adults of all genders ≥ 18 years
  • History of Lyme disease treated with antibiotics, and current PTLDS diagnosed by a physician
  • Evidence of past B. burgdorferi infection based on positive results from both enzyme immunoassay and Western blot testing.
  • Ability to provide informed consent,
  • willing to maintain current PTLDS treatment regimen during participation in the study (if on long-term antibiotics or supplements for PTLDS management).

Who cannot join

  • History of other neurological disorder that in the judgement of the investigator could interfere with the treatment or the interpretation of the results (e.g., epilepsy, history of stroke, tumor, brain tissue damaging pathologies etc.).
  • Current psychotic disorder (e.g., schizophrenia).
  • Current acute illness or infection (e.g. cold or flu).
  • Current or past history of psychiatric illness; PTSD, depression and anxiety are exclusion criteria only if the conditions are so severe as to have required hospitalization in the past 5 years.
  • History of recurrent vaso-vagal syncope
  • Bradycardia defined as resting heart rate <50bpm
Show all 10Show fewer
  • Implanted electronic device (e.g., pacemaker, neurostimulator)
  • Use of immunosuppressive medication such as prednisone, TNF medications within 2 weeks of the visit or anticipated use during the study.
  • Current use of anti-inflammatory steroid use.
  • Pregnancy

About this study

Official title: Pilot, Effect of Respiratory-Gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) on Post-Treatment Lyme Disease Syndrome

This study is to assess if respiratory-gated auricular vagal nerve stimulation (RAVANS) can improve symptoms of post-treatment Lyme disease syndrome

Read the detailed description

Lyme disease is caused by the tick-borne spirochete bacteria Borrelia burgdoferi and is the most common vector borne illness in the US. A subset of individuals with confirmed Lyme disease go on to experience persistent fatigue, pain, and/or neurocognitive difficulties after treatment that are of sufficient severity to impact quality of life and physical functioning. This chronic condition has since been termed post-treatment Lyme disease syndrome (PTLDS). The cause of PTLDS is not known and currently there are no recommended treatments.

We have hypothesized that some cases of PTLDS may be caused by an infection or inflammatory process on or near the neuroimmune vagus nerve, which communicates the detection of peripheral inflammation to the central nervous system and triggers the sickness response circuitry.

Increasing evidence shows that transcutaneous auricular nerve stimulation (taVNS) can significantly reduce multiple symptoms of stress disorder including depression, cognitive impairment, psychomotor retardation, sleep disturbance. Respiratory-gated auricular vagal afferent nerve stimulation(RAVANS), a type of taVNS, which synchronizes stimulation to the respiratory cycle, modulate vagal systems and optimize stimulations and has been shown beneficial effect in pain management.

In this study, we will conduct a randomized, double blinded, sham-controlled pilot study to explore the effect of RAVANS on the symptoms in individuals diagnosed with PTLDS using psychometric measurement, function and cognitive test, and serum biomarkers.

Being tested
respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), Sham RAVANS
Medical subject headings
Post-Lyme Disease Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • respiratory-gated auricular vagal afferent nerve stimulation (RAVANS)Device

    Also called transcutaneous vagus nerve stimulation

    non-painful electrical stimulation of the auricle

  • Sham RAVANSDevice

    sham stimulation

Study groups in NCT04938687
Study groupRoleWhat they receive
RAVANSExperimentalactive RAVANS, 20 minutes each treatment, 3 times per week for 2 weeks
Receives: Device: respiratory-gated auricular vagal afferent nerve stimulation (RAVANS)
Sham stimulationSham comparatorSham-stimulation, 20 minutes each treatment, 3 times per week for 2 weeks
Receives: Device: Sham RAVANS

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire

    This 55-item questionnaire evaluates the frequency, severity, and incidence of Lyme symptoms as well as assessing one's perceived overall health.

    Minimum value:0 Maximum value: 114 The higher number indicates more symptoms

    Measured: Before treatment (baseline) and Post treatment ( at the end of 2-week treatment)

Secondary outcomes (12)
  1. Sedentary Behaviors Questionnaire

    This 18-item questionnaire asks about the amount of time spent engaged in sedentary behaviors on typical weekdays and weekends.

    Minimum:0 Maximum:162 The higher scores mean higher sedentary behaviors

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  2. Fatigue Symptom Inventory

    This non-diagnosis-specific questionnaire measures the severity of fatigue symptoms and how much these factors interfere with the subjects' lives.

    Minimum value:0 Maximum value:127 The higher scores mean higher fatigue symptoms

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  3. Brief Pain Inventory-Pain 24 Hours

    This 15-item questionnaire assesses the location, severity, and type of current pain, using analogue scales and body diagrams. Subscale-pain 24 hours describes the pain at its worst in the past 24 hours.

    Minimum value:0 Maximum value: 10 The higher scores means higher pain level

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  4. Beck Depression Inventory

    This questionnaire evaluates current depressive symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher depressive symptoms

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  5. Beck Anxiety Inventory

    This questionnaire evaluates current anxiety symptoms. Minimum value: 0 Maximum value: 63 The higher scores mean higher anxiety symptoms

    Measured: Before treatment (at baseline) and after treatment (at the end of 2-week treatment)

  6. Pittsburgh Sleep Quality Index

    This 9-item questionnaire assesses sleep quality and patterns of sleep. Minimum value: 0 Maximum value: 21 The higher scores mean poorer sleep quality

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  7. Timed Up and Go

    Measures the time it takes for a person to stand up from a chair, walk 3 meter, turn, walk back, and sit down again.

    Measured: Before treatment ( baseline) and Post treatment (at the end of 2-week treatment)

  8. Time to Complete 4 Meters at Usual Walking Speed,

    Measure usual walk speed

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  9. NIH Toolbox Cognition Battery (NIHTB-CB)

    The following cognitive domains are assessed: executive function (Flanker inhibitory control and attention); cognitive flexibility (Dimensional Change Card Sort); working memory (List Sorting); short-term memory (Picture Sequence), processing speed (Pattern Comparison), Picture vocabulary and Oral Reading Recognition Tests. An overall composite score that combines these outcomes (Total Cognition Composite Score) is reported here.

    The higher value means better cognitive function. A score at or near 100 indicates ability that is average compared with others nationally. Scores around 115 suggest above-average cognitive ability, while scores around 130 suggest superior ability (in the top 2 percent nationally, based on Toolbox normative data). Conversely, a score around 85 suggests below-average cognitive ability, and a score in the range of 70 or below suggests significant impairment.

    Measured: Before treatment (at baseline) and Post treatment (at the end of 2-week treatment)

  10. Serum Level of Inflammatory Cytokines-IL6

    To determine if RAVANS treatment affects the level of inflammation

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

  11. Serum Level of Inflammatory Cytokines-IL10

    To determine if RAVANS treatment affects the level of inflammation

    Measured: Before treatment (at baseline) and after treatment (at the end of 2-week treatment)

  12. Serum Level of Inflammatory Cytokines-TNF Alfa

    To determine if RAVANS treatment affects the level of inflammation

    Measured: Before treatment (baseline) and Post treatment (at the end of 2-week treatment)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jun 2021
  2. Study start31 May 2022
  3. Primary completion11 Aug 2024
  4. Study completion25 Apr 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
randomized, double blinded, sham-controlled
Masking
Double blind
Who is masked
Participant, Outcomes assessor
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04938687
Sponsor's protocol ID
2021P000566
Acronym
RavLyme
Status last verified
Sep 2025
First submitted
9 Jun 2021
Last updated
12 Feb 2026
Data monitoring committee
No
Individual data sharing
No

Publications

  • Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, Zanos TP, Datta-Chaudhuri T, Bouton C, Tracey KJ, Diamond B. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021 Feb;80(2):203-208. doi: 10.1136/annrheumdis-2020-217872. Epub 2020 Nov 3.

    PubMed 33144299
  • Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci. 2000 Dec 20;85(1-3):60-5. doi: 10.1016/S1566-0702(00)00220-4.

    PubMed 11189027
  • Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci. 1998 Nov 15;18(22):9471-9. doi: 10.1523/JNEUROSCI.18-22-09471.1998.

    PubMed 9801384
  • Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, Hodzic E. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS One. 2017 Dec 13;12(12):e0189071. doi: 10.1371/journal.pone.0189071. eCollection 2017.

    PubMed 29236732
  • Garcia RG, Lin RL, Lee J, Kim J, Barbieri R, Sclocco R, Wasan AD, Edwards RR, Rosen BR, Hadjikhani N, Napadow V. Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients. Pain. 2017 Aug;158(8):1461-1472. doi: 10.1097/j.pain.0000000000000930.

    PubMed 28541256
  • Kong J, Fang J, Park J, Li S, Rong P. Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Front Psychiatry. 2018 Feb 5;9:20. doi: 10.3389/fpsyt.2018.00020. eCollection 2018.

    PubMed 29459836
  • Napadow V, Edwards RR, Cahalan CM, Mensing G, Greenbaum S, Valovska A, Li A, Kim J, Maeda Y, Park K, Wasan AD. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 2012 Jun;13(6):777-89. doi: 10.1111/j.1526-4637.2012.01385.x. Epub 2012 May 8.

    PubMed 22568773
  • VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 2013 Sep;81(3):414-23. doi: 10.1016/j.mehy.2013.05.034. Epub 2013 Jun 19.

    PubMed 23790471
  • Zubcevik N, Mao C, Wang QM, Bose EL, Octavien RN, Crandell D, Wood LJ. Symptom Clusters and Functional Impairment in Individuals Treated for Lyme Borreliosis. Front Med (Lausanne). 2020 Aug 21;7:464. doi: 10.3389/fmed.2020.00464. eCollection 2020.

    PubMed 32974369

Questions about this trial

What is this clinical trial studying?

A study testing respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) in people with Post-Treatment Lyme Disease Syndrome, run by Spaulding Rehabilitation Hospital.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Nov 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire (time frame: Before treatment (baseline) and Post treatment ( at the end of 2-week treatment)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04938687, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2026.

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