Effect of Auricular Vagal Nerve Electrical Stimulation on Post-Treatment Lyme Disease Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Auricular Vagal Nerve Electrical Stimulation on Post-Treatment Lyme Disease Syndrome (NCT04938687), a randomized phase not stated study. The primary outcome is Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire.

2. Clinical Question

This is a pilot trial, and the enrollment was 15. That makes the record useful for understanding the intervention schedule, comparator, measurement plan, and the extent of results reported. It does not, by itself, establish whether any difference is reliable, how well it applies to other patients, or whether an observed change would be attributable to stimulation rather than other influences.

3. Trial Design

The trial is listed as randomized, double-masked, and parallel. Participants were assigned within a design comparing active RAVANS with sham stimulation, rather than receiving both interventions in sequence. The registry record lists an enrollment of 15 and marks the study as completed. Its listed start date is 2022-05-31, and its primary completion date is 2024-08-11.

The active and sham schedules were matched in stated duration and frequency: 20 minutes per treatment, 3 times per week for 2 weeks. The registry record identifies both interventions as devices. It does not describe the stimulation parameters, how the sham condition differed from active stimulation, or whether adherence to the planned schedule was assessed.

Random assignment is intended, in general, to reduce systematic differences between groups at the start of a study. Masking is intended, in general, to reduce the influence of expectations or knowledge of assignment on participant reports and study procedures. The record does not specify the randomization method, allocation concealment, or the identities of the masked roles, so those aspects cannot be evaluated from the registry information.

The safety record lists 8 participants at risk in the RAVANS group and 7 in the sham-stimulation group. Those group-specific safety counts should not be treated as a complete account of the primary-outcome analysis population: the registry record does not report the number contributing to each primary measurement or analysis. It also does not report reasons for any missing assessments, withdrawals, or exclusions.

The registry lists secondary measures covering sedentary behavior, fatigue, pain, depression, anxiety, sleep quality, and mobility. The record includes 13 outcome measures and 24 analyses, but does not give enough detail to map every analysis to a specific outcome, time point, or participant set. The trial design is therefore identifiable, while important operational and analysis details are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire, measured over Before treatment (baseline) and Post treatment ( at the end of 2-week treatment).

The primary measure was the Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire. The registry describes it as a 55-item questionnaire assessing the frequency, severity, and incidence of Lyme symptoms, as well as a person's perceived overall health. The score ranges from 0 to 114, and a higher score indicates more symptoms.

The measure was scheduled before treatment at baseline and after treatment at the end of the 2-week treatment period. A repeated symptom measure can describe whether participants' reported symptom burden changes over time. A comparison between randomized groups can help distinguish changes associated with the active intervention schedule from changes also seen with sham stimulation, although the interpretation depends on the analysis and the completeness and precision of the data.

The registry identifies the intended summary as a mean with standard deviation. General statistical context: a mean describes the average score in a group, while a standard deviation describes how dispersed individual scores are around that average. The record does not report the baseline or post-treatment means and standard deviations, nor a single numerical estimate contrasting the groups. It also notes that the primary outcome has several categories or time points and was not reduced to one comparison. Consequently, the scale and timing can be described, but a numerical primary effect cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, double-masked, parallel design. General statistical context: randomization aims to make treatment groups comparable, on average, with respect to both measured and unmeasured characteristics. In a small study, however, chance differences between groups can remain. The record does not report how the random sequence was generated or how assignment was concealed, so those design procedures cannot be assessed.

Masking can reduce the influence of expectations on symptom reporting, especially when outcomes are self-reported. It can also reduce the influence of knowledge of assignment on study conduct. Those are general reasons for masking, not a claim about how masking operated in this trial. The registry labels the study double-masked but does not identify who was masked or describe whether masking was maintained.

The primary measure is continuous: it is a score on a scale, with the registry specifying a mean and standard deviation as the summary. General statistical context: a mean gives a central summary, while a standard deviation describes variability among individual scores. The score's interpretation depends on its direction; in this case, higher values indicate more symptoms. Reporting the baseline and post-treatment group summaries would help readers understand the observed score distributions, while a clearly defined between-group contrast would address the comparative question. Those numerical summaries and a single contrast are not reported in the registry record.

A confidence interval is a general way to communicate uncertainty around an estimated effect. A narrow interval indicates greater precision under the chosen statistical model, while a wide interval indicates less precision. A p-value, in general, measures how unusual data would be under a specified null hypothesis and model; it does not measure the size or clinical importance of an effect. The registry information does not provide a primary estimate, confidence interval, or p-value that can be interpreted for the stated questionnaire comparison.

The record says the primary outcome involved several categories or time points and was not reduced to one comparison. This matters because a comparison must specify what is being contrasted: for example, a post-treatment score, a change from baseline, or a group difference in changes. These are not interchangeable estimands. The registry information does not identify one such contrast as the reported primary result. It would therefore be inappropriate to infer an analysis model or derive an effect from unreported values.

The outcome schedule includes baseline and post-treatment assessment at the end of 2 weeks. General statistical context: repeated measurements can be analyzed in different ways, including comparing final values while accounting for baseline, comparing changes, or modeling measurements over time. Each approach has assumptions and answers a somewhat different question. The registry record does not state which method was used, whether baseline scores were adjusted for, or how within-participant correlation was handled.

Missing data can affect both the precision and potential bias of a treatment comparison. General statistical context: if participants with missing follow-up differ from those observed, an analysis restricted to complete records may not represent the original randomized groups. Methods such as imputation or likelihood-based modeling require assumptions about why values are missing. The registry record does not report missing-data methods, the amount or reasons for missingness, or the participant population used in each analysis.

Over-dispersion is a general issue for count outcomes when observed variability exceeds what a simple count model expects; models that account for extra variability may then be more appropriate. It is not possible to determine whether this issue applies to the continuous questionnaire outcome from the registry description. The record does not report a statistical model for that outcome, and no model should be inferred from the stated mean and standard deviation alone.

Multiplicity arises when several outcomes, time points, or analyses are considered. In general, conducting many statistical tests can increase the chance of finding at least one apparently unusual result even when there is no true effect. Researchers may prespecify a hierarchy, adjust testing thresholds, or treat secondary results as exploratory. The registry lists 13 outcome measures and 24 analyses, but does not report whether multiplicity was addressed or how the analyses were prioritized. The number of listed analyses alone does not reveal the number of independent hypotheses or the adjustment strategy.

The registry also describes a planning illustration based on a fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. General statistical context: such calculations are conditional on assumptions about the effect size, variability, allocation, and statistical test. A planning illustration is not a measure of the study's observed power and does not replace the actual effect estimate and its uncertainty. Because the primary result is not reported as a single comparison, the planning assumptions cannot be connected to an interpretable primary effect from the record.

Finally, the study is identified as a pilot, with enrollment of 15. General statistical context: pilot studies can provide information about feasibility and measurement procedures, but estimates from small studies are often imprecise. That principle does not determine the result of this trial. Here, the primary numerical estimate and its uncertainty are not reported, so statistical precision cannot be evaluated directly.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 24 analyses. The listed secondary measures cover sedentary behavior, fatigue, pain, depression, anxiety, sleep quality, and mobility. The primary questionnaire is assessed at baseline and after the 2-week treatment period, and the registry indicates that the primary outcome has several categories or time points rather than one reduced comparison.

When a study evaluates multiple outcomes or time points, multiplicity is a general concern: the more comparisons considered, the greater the possibility of an apparently notable result arising by chance. A prespecified primary contrast, an adjustment procedure, or a clear distinction between confirmatory and exploratory analyses can help readers interpret a collection of tests. The registry record does not report whether a multiplicity adjustment was used, how the 24 analyses were organized, or how the primary and secondary analyses were prioritized.

The record does not describe the analysis population for the primary outcome. It does not report whether analyses included all randomized participants, only participants who completed treatment, or another defined group. The safety record lists 8 participants at risk in the RAVANS group and 7 in the sham-stimulation group, but those counts do not establish the number included in each efficacy analysis.

Missing-data handling is also not reported. The registry does not state how many baseline or post-treatment questionnaires were available, why any observations were missing, or whether a method such as imputation was used. These details matter because missing outcomes can affect both the estimated group difference and its uncertainty. Without them, the completeness and robustness of the primary comparison cannot be assessed.

These omissions do not demonstrate that the investigators failed to plan analyses or address missing data. They mean only that the relevant procedures and analysis populations are not reported in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety record lists 8 participants at risk in the RAVANS group and 7 in the sham-stimulation group. It reports 0 serious adverse events and 0 deaths in each group. For other adverse events, it reports 3 affected participants in the RAVANS group and 1 in the sham-stimulation group.

These counts describe the entries in the registry record; they do not identify the event types or indicate whether an event was mild, moderate, or severe. The record does not report when events occurred, how long they lasted, whether participants stopped treatment, or whether investigators considered any event related to the device or procedure. It also does not provide detail on how adverse events were collected or categorized.

General statistical context: adverse-event counts are descriptive unless accompanied by a defined comparison and sufficient information about event ascertainment and follow-up. With a small enrollment, the absence of recorded serious events should not be read as proof that serious events cannot occur. Likewise, the difference in the listed counts of other adverse events does not establish that one intervention caused more events than the other. The registry record provides limited safety counts, not a causal safety analysis.

12. What the Result Does, and Does Not, Mean

The registry record establishes that a completed pilot trial was designed to compare active RAVANS with sham stimulation for post-treatment Lyme disease syndrome. The primary symptom measure, its score direction, and its scheduled measurement times are described. The active and sham schedules are also stated. These details make the research question and intended comparison understandable.

The record does not provide a single numerical primary-outcome comparison. It therefore does not establish the size, direction, or precision of the difference between groups on the Horowitz questionnaire. The absence of a reported numerical comparison should not be interpreted as evidence of no difference, nor as evidence of a benefit. No conclusion about the primary symptom result can be drawn from the registry information alone.

The listed secondary outcomes show that the study assessed more than the primary symptom questionnaire, including fatigue, pain, mood, sleep, sedentary behavior, and mobility. Their presence in the registry is not evidence of a particular finding. The numerical results and detailed analyses for those measures are not reported in the information available for this analysis.

The safety entries report no serious adverse events and no deaths, alongside other adverse events affecting 3 participants assigned to RAVANS and 1 assigned to sham stimulation. These counts do not identify event types or establish whether events were caused by treatment. They should be read as limited descriptive information from a pilot study, not as a definitive comparison of risks.

General statistical context: an effect estimate is more informative when considered together with its uncertainty, the outcome's meaning, the analysis population, and the study's limitations. In this case, the primary estimate and uncertainty are unavailable in the registry record. The trial's randomized design is relevant, but the enrollment of 15 and the unreported analysis details constrain interpretation. The record supports describing what was planned and what safety counts were posted; it does not support a claim that the intervention does or does not work.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of why a design description and a result description answer different questions. The registry identifies randomization, double masking, a parallel comparison, the treatment schedule, and a patient-reported primary measure. Those features describe how the study was intended to address its question, but they do not tell readers what the primary comparison found.

The primary endpoint is defined in useful terms: the questionnaire assesses Lyme symptom frequency, severity, incidence, and perceived overall health; its score ranges from 0 to 114, with higher scores indicating more symptoms. The planned baseline and post-treatment assessments also make the timing of measurement clear. Yet without group-level scores or a single between-group estimate, readers cannot evaluate the observed effect or its precision. Endpoint definition is necessary for interpretation, but it cannot replace outcome results.

The registry lists 13 outcome measures and 24 analyses. This makes clear why transparent reporting of the prespecified primary contrast, secondary analyses, missing-data approach, and multiplicity strategy matters. General statistical context: when several outcomes and time points are assessed, readers need to know which comparisons were planned as primary and how other results should be interpreted. The record does not report those details sufficiently to assess the analysis strategy.

The study's enrollment of 15 also highlights the importance of uncertainty. General statistical context: smaller studies tend to provide less precise estimates, although precision depends on the data variability and analysis as well as sample size. Without an effect estimate and confidence interval, the degree of uncertainty cannot be quantified. The posted safety counts are useful as descriptive information but do not resolve that limitation.

For biostatisticians and clinical researchers, the key lesson is that registry transparency should connect the question, the estimand, and the reported result. A clear endpoint and trial design allow readers to understand what was intended; a defined contrast and its uncertainty are needed to understand what the data show. In this record, the former is substantially clearer than the latter.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for interpretation is that the registry record does not report a single numerical primary-outcome comparison. It gives the questionnaire description, score range, direction, and time frame, but not group-specific scores or an effect estimate with uncertainty. The record explicitly indicates that the primary outcome spans several categories or time points and was not reduced to one comparison.

The enrollment was 15, and the safety record lists 8 participants at risk in the RAVANS group and 7 in the sham-stimulation group. The record does not state how many participants contributed primary-outcome data at each time point. It also does not report withdrawals, adherence, missing observations, or the analysis population. These omissions limit assessment of whether the posted groups and outcome data represent the intended randomized comparison.

Although the study is labeled randomized and double-masked, the registry does not describe the randomization process, allocation concealment, or which roles were masked. It does not describe the active and sham stimulation parameters beyond the treatment schedules. Consequently, readers cannot evaluate these implementation details from the registry record.

The registry lists many outcomes and analyses but does not report a clear multiplicity strategy or a complete mapping of analyses to outcomes and time points. Numerical secondary results are also not available in the information used for this analysis. The safety record provides affected-participant counts but not adverse-event terms, severity, timing, or judged relationship to treatment.

These are limitations of the information reported in the registry record. They do not establish that the study lacked procedures or that unreported findings were favorable or unfavorable. They restrict what can be concluded from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Auricular Vagal Nerve Electrical Stimulation on Post-Treatment Lyme Disease Syndrome — NCT04938687.
• Registry record last updated 2026-02-12; status last verified 2025-09.
• Results first posted 2025-11-10.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04938687 is a completed randomized, double-masked, parallel pilot trial of respiratory-gated auricular vagal afferent nerve stimulation for post-treatment Lyme disease syndrome. The listed enrollment is 15. The active RAVANS and sham schedules were each 20 minutes per treatment, 3 times per week for 2 weeks.

The primary measure was the Horowitz Lyme-Multiple Systemic Infectious Disease Syndrome Questionnaire, assessed at baseline and after treatment. Higher scores indicate more symptoms on a scale from 0 to 114. The registry record does not report a single numerical primary-outcome comparison, and key analysis details, including missing-data handling and analysis populations, are not reported.

The safety record lists no serious adverse events and no deaths in either group. Other adverse events affected 3 participants in the RAVANS group and 1 in the sham-stimulation group. Event types and relationships to treatment are not reported in the registry record. The posted information supports describing the design and limited safety counts, but not judging the magnitude or precision of the primary outcome.