Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus (NCT02917265), a randomized phase 2 study. The primary outcome is Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA).

2. Clinical Question

The trial asks whether participants assigned to active tVNS differ from those assigned to sham stimulation on a composite measure of SLE disease activity. The intervention and comparator both use a TENS unit at the external ear; the registry distinguishes them by whether the application area is innervated by the auricular branch of the vagus nerve. The record does not describe further treatment procedures or how the sham was designed to feel to participants.

The primary endpoint is a BICLA response at 12 weeks. The registry also lists improvement in disease activity by the SLE Responder Index (SRI-4) and improvement in heart rate variability (HRV) as secondary outcomes. Their definitions, analysis details, and group results are not reported in the registry record. The central clinical research question can therefore be stated from the design and outcome definition, but the posted record does not provide the primary comparison needed to judge the observed response difference.

3. Trial Design

This is a randomized, parallel-group phase 2 trial comparing TENS for vagus stimulation with TENS for sham stimulation in participants with active SLE. The brief summary describes a 3-month double-blinded randomized controlled study. The registry classifies masking as quadruple; which people or roles were masked is not reported in the registry record. Allocation procedures, including how the random sequence was generated and concealed, are not reported in the registry record.

The registry records enrollment of 7 participants. It lists the study as terminated. The start is recorded as 2015-11 and primary completion as 2017-05. The reason for termination, whether recruitment stopped early, and whether the planned enrollment or follow-up was changed are not reported in the registry record. The sponsor is Aikaterini Thanou.

The two interventions differ in the TENS application site: the active intervention is applied to an external-ear area innervated by the auricular branch of the vagus nerve, while the sham is applied to an area described as devoid of vagus innervation. The registry describes the primary endpoint timeframe as 12 weeks, while the brief summary characterizes the study as lasting 3 months. Details such as treatment frequency, session duration, adherence monitoring, and permitted co-interventions are not reported in the registry record.

The record lists 5 outcome measures and 1 analysis, but it does not provide a complete statistical analysis plan. The registry does not report a sample-size justification, planned enrollment target, interim-analysis plan, analysis populations, or the method used to handle missing outcome data. These omissions matter because a randomized design alone does not explain how a small trial’s estimates were to be produced or interpreted. The design identifies the intended comparison, but it does not establish that outcome data were available for every randomized participant or that the planned analysis was completed.

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.

Before assignment: Screening and randomization occurred at the same visit. One individual failed screening due to severe depression.

Overall Study

Reasons for not completing this period:

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 Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA), measured over 12 weeks.

The primary endpoint is improvement in SLE disease activity assessed by BICLA at 12 weeks. The registry describes the endpoint as the percentage of participants on active versus sham tVNS with improvement, while its parameter classification is a count of participants. The record does not give group-specific BICLA response counts or percentages, so the primary result cannot be described from the posted data.

BICLA is a composite response definition drawing on several disease-activity measures. To qualify, a participant must have all BILAG A scores improve to B, C, or D and all BILAG B scores improve to C or D. The participant must also have no new BILAG A score and not more than one new BILAG B score, no worsening in the baseline SLEDAI total score, and no worsening in the Physician Global Assessment (PGA), with worsening defined as less than 10% from baseline in the registry description. The criteria also exclude participants who initiate non-protocol treatments or discontinue the study prematurely.

Composite endpoints can represent change across multiple aspects of a condition rather than relying on a single measure. In general, requiring several criteria to be met makes the response definition specific to the chosen combination, but a composite result does not reveal which component drove a response or how each component changed. BICLA is used as the registry’s primary operational definition of improvement; its listed score ranges are BILAG 0 to 96, SLEDAI 0 to 105, and PGA 0-3, with higher scores indicating more active disease. How component outcomes were analyzed separately is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help translate trial observations into estimates that can be compared across randomized groups. In this record, the intended contrast is active tVNS versus sham stimulation, and the primary outcome is a participant-level BICLA response at 12 weeks. The registry identifies a count-of-participants parameter for that endpoint. The actual analysis method, effect measure, uncertainty interval, and hypothesis test are not reported in the registry record.

What a binary response means

In general, a binary endpoint classifies each participant into one of two categories, such as meeting or not meeting a prespecified response definition. A count records how many participants fall into a category; a percentage expresses that count relative to the group size. The registry’s endpoint title describes a percentage, while its parameter classification describes a count. Without posted group counts and denominators, neither group response percentages nor a between-group contrast can be evaluated. No such calculations can be reconstructed from the record.

BICLA is not a single symptom score. It combines requirements involving BILAG, SLEDAI, and PGA, as well as treatment and discontinuation conditions. A participant must satisfy every stated component to meet the response definition. This makes the endpoint’s interpretation dependent on the full rule, rather than on a favorable change in only one instrument. In general, a composite outcome can summarize several dimensions, but a single overall response result does not by itself show how each dimension contributed. Component-level results and the handling of individual criteria are not reported in the registry record.

Comparing randomized groups

For a binary endpoint, analyses commonly compare response frequencies between randomized groups. General choices include a difference in response proportions, a ratio of response proportions, or a model-based estimate. Each answers a somewhat different question and carries assumptions about how data are represented. The record does not state which comparison measure or statistical model was planned or used. It therefore would be inappropriate to assign a particular method to this trial or to infer a numerical effect.

Random assignment supports a group comparison by reducing systematic differences at the point of assignment, in expectation. It does not ensure that a very small trial will have balanced groups on every characteristic, and it does not resolve missing outcome data or deviations from assigned treatment. The registry reports randomized allocation but does not report the randomization method, stratification factors, baseline group characteristics, adherence, or treatment crossover. These details are necessary for a fuller assessment of how the planned comparison was implemented.

Uncertainty and small samples

In general, an estimate from a trial is more informative when accompanied by an uncertainty interval. A confidence interval describes a range of values compatible with the data and the statistical model at a stated confidence level; it does not guarantee that the true effect lies in that range. When the observed number of responses is limited, estimates can be unstable and intervals can be wide. The registry record does not report a primary estimate or confidence interval, so its precision cannot be assessed.

Small samples can also make some standard statistical approximations less dependable, particularly for outcomes represented by counts in groups. Alternative methods may be considered in general, but the analysis choice depends on the design, data, and estimand. The registry does not report a method for the BICLA comparison, so no statement can be made about whether an exact method, a model, or an approximation was used. The listed enrollment is not a substitute for outcome counts and cannot determine which analysis would be appropriate.

Multiplicity and secondary outcomes

Multiplicity arises when several outcomes, time points, subgroups, or analyses are tested. If many comparisons are considered, the chance of finding at least one apparently notable result by chance may increase unless the analysis plan addresses that issue. The registry lists secondary outcomes for SRI-4 improvement and HRV improvement and records 5 outcome measures overall. It does not report a multiplicity adjustment, a hierarchy among outcomes, or which analyses were prespecified. Thus, the family of statistical tests and any control of false-positive findings are not reported in the registry record.

Missing data and analysis populations

Missingness is important when participants lack an outcome measurement or discontinue before the endpoint visit. General strategies include analyzing available outcomes, imputing missing values under explicit assumptions, or defining a composite rule for certain events. Each strategy can lead to different interpretations. The BICLA definition itself includes no premature study discontinuation and no initiation of non-protocol treatments as response conditions, but the registry does not state how these events were recorded or incorporated into the analysis. The approach to other missing data is not reported in the registry record.

An analysis population defines which participants contribute to a particular estimate. Examples in general include analyzing participants according to randomized assignment or restricting analysis to those who completed treatment, but these approaches answer different questions and can be affected differently by post-randomization events. The registry does not identify the primary analysis population or report whether all randomized participants contributed to the outcome analysis. No estimate can be reconstructed without those data and decisions.

Planning versus observed results

Sample-size planning and observed trial results serve different purposes. A planning illustration uses assumptions about an effect, variability or event frequency, significance level, allocation, and a desired power level to describe a hypothetical design. It is not an observed-power calculation and cannot establish what the completed trial demonstrated. The registry record does not report the trial’s sample-size justification or numerical planning assumptions. Any planning illustration based on an observed effect should be read as a hypothetical design calculation, not as a trial result. No planning estimate or recalculated comparison is reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including the primary BICLA response and secondary outcomes for SRI-4 improvement and HRV improvement. It records 1 analysis, but this does not describe the full analysis plan or establish how many statistical tests were conducted. The hierarchy among outcomes, prespecified contrasts, any subgroup analyses, and any adjustment for multiple testing are not reported in the registry record.

Multiplicity matters in general because examining multiple outcomes, time points, or analyses can increase the chance that at least one result appears unusual by chance. A prespecified hierarchy or statistical adjustment can address some multiplicity concerns, but the registry does not describe such procedures. Since outcome results are not reported, the record also does not show whether any nominal or adjusted inferential results were presented.

Missing-data handling is not reported in the registry record. This includes whether data were missing for any outcome, whether participants who discontinued were retained in an analysis, and what assumptions or methods were used for missing measurements. The endpoint definition states that premature study discontinuation and initiation of non-protocol treatments do not satisfy BICLA response criteria. How those situations were operationalized in the analysis is not reported.

The primary analysis population is also not reported in the registry record. It is therefore unclear whether the analysis was based on everyone randomized, participants who received assigned stimulation, participants with an available 12-week assessment, or another defined group. These distinctions affect the meaning of an estimated group contrast. Without the analysis population, missing-data method, and outcome results, the record does not permit a complete assessment of bias or robustness.

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 registry reports serious adverse events for 0 participants among 5 at risk in the TENS for vagus stimulation group and 0 participants among 2 at risk in the TENS for sham stimulation group. It reports other adverse events for 4 participants among 5 at risk in the vagus-stimulation group and 1 participant among 2 at risk in the sham group. Deaths are reported as 0 in each group. These are participant counts, not descriptions of event type, duration, severity, or causal relationship to stimulation.

In general, an adverse-event count records events or participants with events according to the registry’s reporting structure; a count alone does not establish that an intervention caused an event. The record does not provide the specific non-serious event terms, event timing, exposure duration, or attribution assessments. The serious-event terms list is empty. It is also not reported whether participants could experience more than one event or how recurrent events were counted. The small group sizes mean the counts describe only the participants represented in this record and should not be read as precise estimates of event frequency in a broader population.

These safety figures do not provide evidence about the primary BICLA response. Nor do they settle comparative safety: the record does not report enough information about event definitions, exposure, or follow-up to characterize differences beyond the posted counts. They should be read descriptively, without inferring causation or generalizing beyond this trial record.

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

The record establishes that a randomized parallel-group phase 2 trial was conducted to compare active tVNS with sham stimulation for active SLE, with BICLA response at 12 weeks as the primary endpoint. It also gives the response criteria, secondary outcomes of interest, enrollment, status, and adverse-event counts. These details make the intended research question identifiable.

The record does not report the group-specific BICLA results. It therefore does not show how many participants met the response definition, the estimated difference between groups, or the precision of any comparison. The absence of a posted result is not evidence that the treatments had the same outcome, and it is not evidence that one group did better. It simply leaves the primary result unavailable in the registry record.

The secondary outcomes are listed, but their findings are not reported. It is not possible to infer disease-activity changes from the SRI-4 listing or changes in HRV from the HRV listing. Likewise, the adverse-event counts provide a limited description of reported events, not a causal assessment or a complete account of safety.

In general, a trial result is interpreted in light of its estimate, uncertainty, design, analysis choices, outcome definitions, and completeness of follow-up. Here, several of these elements are not reported in the registry record, including the statistical plan, analysis population, missing-data approach, and primary effect estimate. Consequently, the available information can describe the study’s structure and the intended endpoint but cannot establish the magnitude or direction of the primary comparison.

The registry status is terminated, but the reason is not reported in the registry record. The available information does not establish whether termination was related to recruitment, funding, safety, operational issues, or another cause. No explanation should be inferred from the status label alone. The findings that can responsibly be stated are restricted to the registry entries recorded: the trial’s design and endpoint definition, its enrollment and status, and the posted safety counts.

13. Why This Trial Matters Statistically

This trial is statistically notable because the intended comparison is clear while the outcome information needed to estimate that comparison is absent from the registry record. It illustrates the difference between a prespecified outcome definition and an observed outcome result. A detailed response rule can clarify what investigators count as improvement, but it cannot reveal how many participants met that rule or how the randomized groups compared.

The endpoint is composite: it combines BILAG, SLEDAI, and PGA criteria with restrictions on new disease activity, non-protocol treatment, and premature discontinuation. Such definitions can make a response measure more comprehensive, but interpretation depends on all components and on consistent implementation. Without outcome results or component-level reporting, the record does not show which aspects of the definition shaped any observed responses.

The enrollment of 7 and terminated status also make transparent reporting of estimates and uncertainty especially important. General statistical reasoning cautions that results based on few participants may be imprecise, but precision cannot be evaluated without group outcome data and an interval estimate. Enrollment alone is not an efficacy result and cannot substitute for the missing comparison.

The record also provides an example of why trial registration fields should be read separately: design classifications, outcome definitions, safety counts, and inferential results answer different questions. Randomization describes the intended allocation structure; it does not itself provide the outcome estimate. Safety counts do not answer the primary disease-activity question, and listing secondary measures does not supply their results. The statistical lesson is not a conclusion about treatment, but the importance of complete reporting of outcomes, analysis methods, and uncertainty so that readers can distinguish what was planned from what was observed.

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 main trial-specific limitation for statistical interpretation is that the registry record does not report primary BICLA outcome results. There are no group-specific response counts or percentages, treatment-effect estimate, confidence interval, or p-value. Secondary outcome results for SRI-4 and HRV are also not reported in the registry record. The direction, magnitude, and precision of the intended comparisons therefore cannot be evaluated.

Enrollment was 7, and the study is listed as terminated. The reason for termination, the planned enrollment, whether enrollment was stopped before a target, and the consequences for follow-up are not reported in the registry record. These details would help establish how complete the trial was relative to its intended design, but they cannot be inferred from the status alone.

The registry reports randomized allocation and quadruple masking, while the brief summary calls the study double blinded. The identities of masked roles and details of allocation generation or concealment are not reported in the registry record. Baseline characteristics, adherence, treatment exposure, withdrawals, and outcome availability by group are also not reported. These gaps limit assessment of comparability after randomization and of possible effects of missing or incomplete follow-up.

Although the primary endpoint criteria are described, the record does not report component-level results, analysis populations, statistical methods, multiplicity procedures, or missing-data handling. Nor does it report a sample-size justification. The safety information is limited to participant counts, with no specific non-serious event terms or additional event context. These limitations constrain interpretation to the design and counts explicitly recorded; they do not support reconstructing unreported efficacy findings or explaining the trial’s termination.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus — NCT02917265.
• Registry record last updated 2020-03-03; status last verified 2019-09.
• Results first posted 2019-10-10.
• 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

NCT02917265 is a randomized, parallel-group phase 2 trial of transcutaneous vagus nerve stimulation for active systemic lupus erythematosus. It compares TENS applied to an external-ear area innervated by the auricular branch of the vagus nerve with TENS applied to an area described as devoid of vagus innervation. The primary endpoint is BICLA response at 12 weeks. The brief summary describes a 3-month study, and the registry records quadruple masking while the summary calls it double blinded.

The record lists enrollment of 7, status as terminated, and primary and secondary outcome measures. It reports adverse-event counts by group but does not report primary BICLA results or secondary outcome results. Details of the analysis plan, missing-data handling, and reason for termination are not reported in the registry record. The posted information defines the intended comparison but does not permit an estimate of its primary outcome contrast.