tAN to Mitigate Withdrawal Behaviors in Neonates: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for tAN to Mitigate Withdrawal Behaviors in Neonates (NCT04588519), a na na study. The primary outcome is Number of Subjects With no Adverse Events Related to Bradycardia (HR < 80 Bpm), Worsening of Swallowing or Feeding, Skin Irritation, or Elevation of Neonatal Infant Pain Scores..

2. Clinical Question

The study summary describes an early, first-in-human-neonates pilot designed to examine tAN use alongside oral morphine and its potential relationship to morphine weaning. Duration of morphine weaning and length of hospital stay are listed as secondary outcomes. However, the registry record does not report results for those outcomes or the result for the stated primary endpoint. The available safety counts therefore do not answer the full clinical question, and the single-group design does not provide a like-for-like control comparison.

3. Trial Design

This was a completed, single-group, open-label pilot with enrollment of 8. The registry lists phase as NA, allocation as NA, and masking as NONE. It does not list a concurrent control arm. Without a comparator, observations describe participants in the intervention group; they cannot by themselves estimate how outcomes would have differed under another treatment or usual care.

The intervention was the Spark Biomedical Roo Transcutaneous Auricular Neurostimulation System. The arm description specifies a pulse width of 250ms, with channel 1 at 5 Hz and mean intensity 0.3±0.2 mA, and channel 2 at 100 Hz and mean intensity 0.6±0.2 mA. The study summary describes sticker-like patches worn in and around the ear during the withdrawal period, delivering electrical pulses to the skin and underlying cranial nerves.

The primary outcome was a count of participants with no adverse events in specified categories during 12 days. The listed secondary outcomes were duration of morphine weaning and length of hospital stay. The record gives a start date of 2020-05-30, a primary completion date of 2020-12-01, and a status of COMPLETED. Completion describes the study status; it does not establish that results for every planned outcome are available. The registry record does not report a detailed protocol, recruitment procedures, or the planned statistical analysis. Because this is a single-group study, its design is descriptive rather than a randomized comparison.

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 Number of Subjects With no Adverse Events Related to Bradycardia (HR < 80 Bpm), Worsening of Swallowing or Feeding, Skin Irritation, or Elevation of Neonatal Infant Pain Scores., measured over 12 days.

The primary endpoint is the number of participants with no adverse events related to bradycardia (heart rate below the stated threshold of HR < 80 bpm), worsening of swallowing or feeding, skin irritation, or elevation of Neonatal Infant Pain Scores. Its timeframe is 12 days. This is a safety-focused endpoint: it groups several specified events and asks whether participants remained free of those events over the stated period.

In general, a count endpoint is a straightforward way to describe how many participants meet a defined outcome. Its interpretation depends on the definition of an event, the observation period, and the number of participants assessed. For a composite endpoint such as this one, the individual components may differ in nature and importance; the combined count does not show which component occurred unless those component results are separately reported.

The registry record does not report the primary endpoint count. The safety figures list 0 participants with serious adverse events and 1 participant with other adverse events, but they do not identify whether the other event matched a primary-endpoint category or was considered related to tAN. Those figures therefore cannot be treated as the reported result for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a single-group study and provides safety counts, but does not report an inferential analysis for the primary or secondary outcomes. The statistical concepts below are general explanations; they should not be read as methods confirmed for this study unless explicitly identified in the registry record.

What does a participant count represent?

A count records how many participants meet a specified definition. For a binary outcome, each participant is classified according to whether the defined event or condition is present. A count is easiest to interpret alongside the number of participants assessed, the outcome definition, and the observation period. The posted safety information gives participants at risk and counts with serious and other adverse events. The primary endpoint has a separate definition—no adverse events in specified categories over 12 days—but its result is not reported in the registry record.

Counts are descriptive. They do not, on their own, establish that an event was caused by an intervention. Judgments about attribution, the timing of an event, its severity, and whether it meets a particular endpoint definition require information beyond a count. The registry record does not list the terms for the other adverse event or link that event to the primary endpoint categories.

Why does the single-group design matter?

A comparison of outcomes between groups can help estimate whether outcomes differ under alternative treatment conditions. In a single-group study, there is no concurrent control group to provide that contrast. Observations may describe what occurred during treatment, but they cannot separate the intervention's contribution from other factors, such as the course of the condition or other care. This is especially important for outcomes such as duration of morphine weaning and length of hospital stay, which are listed but have no reported results in the registry record.

Open-label status means the registry lists masking as NONE. In general, lack of masking can affect outcomes that rely on judgment or reporting, because participants or study personnel know which intervention is being used. The record does not describe outcome-assessment procedures, so it is not possible to determine how such considerations were addressed.

What would an uncertainty interval tell readers?

In general, a confidence interval expresses the range of values compatible with an estimate under a specified statistical model. It communicates precision as well as the estimated result. Narrower intervals generally indicate greater precision, while wider intervals indicate more uncertainty. No confidence interval for the safety counts or clinical outcomes is reported in the registry record. The counts alone therefore do not quantify the uncertainty around an estimated event frequency.

With a small enrollment, estimates can be imprecise, particularly for uncommon events. This general point does not produce an additional estimate for this study. No unreported event rate or interval should be inferred from the posted counts.

What can planning calculations establish?

Planning calculations are hypothetical illustrations of the sample size that might be needed under stated assumptions; they are not results observed in a trial. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They also define the effect to detect as a stated fraction of the observed effect. For time-to-event outcomes, the planning description refers to a total number of events; for other outcomes, it refers to participants per arm.

These assumptions describe planning illustrations, not the design of this single-group study. The registry record does not report a trial-specific sample-size justification or the observed effect needed to interpret such an illustration. A planning calculation cannot establish that a study had a given probability of detecting an effect after the fact. It is not observed power, and it does not replace outcome estimates with uncertainty intervals.

What analysis details are unavailable?

The registry lists 4 outcome measures and 0 analyses. It does not report statistical tests, model choices, adjustment methods, confidence intervals, or how any analysis handled missing observations. It also does not report a statistical analysis plan or identify an analysis population. As a result, the posted counts should be described as recorded counts rather than as the output of a reported inferential model.

In general, an analysis plan specifies how outcomes will be defined and analyzed before results are examined. This can reduce ambiguity about which comparisons, models, and outcome definitions will guide interpretation. The registry record does not report such a plan. It is therefore not possible to assess whether the posted outcome information follows a prespecified analysis or how the analysis would address alternative explanations.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Active Transcutaneous Auricular Neurostimulation")
n      <- c(8)
events <- c(7)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Active Transcutaneous Auricular Neurostimulation  8  7  87.5  47.3  99.7  52.9  97.8  51.8  97.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures, including the primary safety endpoint and secondary outcomes for duration of morphine weaning and length of hospital stay. It reports 0 analyses. The record does not describe how many outcomes were intended for formal testing, how outcomes were prioritized in analysis, or whether any adjustment for multiple testing was planned. These details are not reported in the registry record.

In general, examining multiple outcomes can increase the chance of finding an apparently notable result by chance when many statistical tests are conducted. Multiplicity methods can address that issue, but the appropriate approach depends on the analysis plan and the role of each outcome. Since no outcome-level tests or statistical plan are reported, it is not possible to assess multiplicity handling or to interpret a family of statistical tests.

The registry record also does not report how missing outcome data were handled, whether any participants lacked particular assessments, or which analysis population was used. Enrollment of 8 does not establish that every outcome was assessed for every participant. Without those details, the completeness of outcome data and the population underlying any result cannot be evaluated.

These absences are not evidence that a particular method was or was not used outside the registry record. They limit what can be concluded from the posted information: no missing-data strategy, analysis population, or multiplicity procedure is documented.

12. 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

For the active tAN group, the registry lists 8 participants at risk for serious adverse events and 8 at risk for other adverse events. It reports serious adverse events for 0 participants, other adverse events for 1 participant, and deaths for 0 participants. The record does not list any top serious adverse-event terms.

These categories should be kept separate. The serious-event count is not the same as the count for other adverse events, and neither count is automatically the result for the primary endpoint. The primary endpoint concerns no events in particular categories—bradycardia (HR < 80 bpm), worsening of swallowing or feeding, skin irritation, or elevation of Neonatal Infant Pain Scores—during 12 days. The registry does not identify whether the other adverse event matched one of those categories or was related to tAN.

In general, zero recorded events in a group does not establish that the underlying risk is zero. A small group and a limited observation period may leave uncertainty about uncommon events. The registry record provides counts, not a comparative safety estimate, and lists no control group. These figures therefore describe the recorded safety information for this study rather than establish comparative safety.

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

The registry record describes an open-label pilot of tAN in neonates with opioid withdrawal, with enrollment of 8 and no concurrent comparison group. It reports 0 participants with serious adverse events, 1 participant with other adverse events, and 0 deaths in the active tAN group. These counts are useful as a limited description of the safety information recorded for the group.

The counts do not answer the stated primary endpoint because the registry does not report how many participants had no adverse events in the endpoint's specified categories during 12 days. Nor do they show which event occurred, whether it was related to treatment, or whether it met one of those categories. The serious and other adverse-event counts should not be substituted for the primary endpoint result.

The registry lists duration of morphine weaning and length of hospital stay as secondary outcomes, but their results are not reported in the registry record. There is also no reported analysis comparing outcomes with a control group. Consequently, the posted information cannot establish whether tAN affected withdrawal behaviors, morphine use, the time needed to wean morphine, or time in hospital.

In general, a pilot can contribute descriptive information and help identify questions for further study. That role is different from demonstrating a treatment effect. A single-group design cannot rule out explanations other than the intervention, and a small enrollment provides limited precision. The completion status does not change these interpretive limits or substitute for missing outcome results.

The appropriate reading is narrow: the record documents the study design and the stated adverse-event counts, while leaving the primary endpoint and secondary clinical outcomes without reported results. Neither benefit nor lack of benefit can be inferred from those missing results.

14. Why This Trial Matters Statistically

This study is statistically notable as a first-in-human-neonates, open-label pilot with a single group. Such a design makes it especially important to distinguish descriptive safety reporting from evidence of a comparative treatment effect. The registry's safety counts describe what was recorded in the intervention group, but without a control group they do not estimate how those counts compare with another care strategy.

The primary endpoint is framed as a count of participants without specified adverse events over 12 days. That definition highlights the importance of keeping an endpoint's exact criteria distinct from broader safety summaries. The registry reports counts for serious and other adverse events but does not report the primary endpoint result or identify the other event. The distinction prevents an apparently simple count from being overinterpreted.

Enrollment of 8 also illustrates a general precision issue: when a study includes few participants, each observation has substantial influence on the overall count. This makes clear outcome definitions, complete reporting, and uncertainty estimates particularly valuable. The record does not report confidence intervals or inferential analyses, so the precision of estimates cannot be assessed statistically.

Finally, the listed secondary outcomes—duration of morphine weaning and length of hospital stay—are relevant to the study's stated aims, yet their results are not reported in the registry record. The contrast between listed outcomes and absent outcome results is itself important for statistical interpretation: a completed study record does not automatically provide enough data to assess each research question. The available record supports a cautious description, not a comparative conclusion.

15. 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 design limitation is the absence of a control group. With a single group and no randomized comparison, observed outcomes cannot be separated from other influences. The registry lists allocation as NA and masking as NONE. Open-label assessment can also matter for outcomes involving clinical judgment or participant reporting, while the record does not describe how these outcomes were assessed.

Enrollment was 8, limiting the amount of information available to characterize outcomes and uncommon adverse events. The registry does not report confidence intervals or other uncertainty estimates for the safety counts. The primary endpoint result is not reported, and the secondary outcome results for morphine-weaning duration and hospital stay are also not reported. The other adverse event is not identified, so its relationship to the primary endpoint categories cannot be determined from the record.

The registry lists 4 outcome measures and 0 analyses, but does not report the statistical analysis plan, analysis population, handling of missing data, or approach to multiplicity. It is therefore not possible to assess whether all enrolled participants contributed data to each outcome or how planned analyses were carried out. No trial-specific sample-size justification is reported in the registry record.

These limitations concern what can be learned from the posted registry information. They do not establish that unreported procedures were absent; those details are simply not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: tAN to Mitigate Withdrawal Behaviors in Neonates — NCT04588519.
• Registry record last updated 2022-12-28; status last verified 2022-12.
• Results first posted 2022-12-28.
• 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.

19. Record Summary

NCT04588519 is a completed, open-label, single-group pilot of the Spark Biomedical Roo Transcutaneous Auricular Neurostimulation System in neonates with opioid withdrawal. The registry reports enrollment of 8, phase NA, allocation NA, and masking NONE. The primary endpoint concerns participants without specified adverse events during 12 days. Secondary outcomes are duration of morphine weaning and length of hospital stay.

For the active tAN group, the registry reports 0 participants with serious adverse events, 1 with other adverse events, and 0 deaths. It does not report the primary endpoint result, the secondary outcome results, statistical analyses, or a concurrent control comparison. The record therefore supports a limited description of the study design and safety counts, not conclusions about comparative effects.