Treatment of Neonatal Abstinence Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Neonatal Abstinence Syndrome (NCT01723722), a randomized phase 4 study. The primary outcome is Length of Treatment With Opioid Medication.

2. Clinical Question

3. Trial Design

The registry record identifies this as a Phase 4, randomized, open-label, parallel-group trial. The trial status is completed, with 40 participants enrolled. Its listed condition is Neonatal Abstinence Syndrome. Eastern Maine Medical Center is named as the sponsor. The record lists a start date of 2007-01 and primary completion in 2009-09.

The randomized comparison involved two treatment groups. One group received phenobarbital and methadone; the other received phenobarbital and diluted deodorized tincture of opium. The brief summary says phenobarbital was the initial medication used to stabilize neonatal withdrawal. The subsequent opioid medications were compared with respect to treatment length. Because the trial was open label, masking is recorded as none. Details of the randomization procedure, including how the sequence was generated or concealed, are not reported in the registry record.

The primary outcome is length of treatment with opioid medication, measured in days and summarized as a mean with standard deviation. The outcome timeframe is listed as up to 12 months, while the primary population is described as completion of treatment. The registry record reports 20 participants in each group for this outcome. The posted results do not describe participant flow, exclusions from the analysis, or whether all randomized participants contributed an outcome.

The registry record lists one outcome measure and no secondary outcomes with posted results. It does not provide details of the original sample-size rationale, the trial's planned statistical analysis, or any interim analyses. Those omissions limit the ability to compare the posted summary with a prespecified analysis plan.

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: Exclusion for other medical conditions causing withdrawal symptoms, gestation less than 35 weeks

Overall Study

Analysis population for the primary outcome, as defined in the registry: Completion of treatment

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 Length of Treatment With Opioid Medication, measured over Up to 12 months.

The primary endpoint is length of treatment with opioid medication, recorded in days. The registry record describes the measure as a mean and gives the population as completion of treatment. The outcome timeframe is listed as up to 12 months. The posted group summaries are 19.1 days for the group receiving dDTO after phenobarbital and 17.7 days for the group receiving methadone after phenobarbital. The corresponding standard deviations are 8.8 and 10.0 days.

Duration is a direct measure of how long the opioid-medication treatment continued under the study's treatment approach. It can therefore summarize a practical aspect of treatment exposure, while not by itself describing symptom severity, the course of withdrawal, or other aspects of care. The trial's stated purpose was to compare the length of treatment between the two drug combinations. The endpoint is not a measure of all treatment received, nor does the registry record give a definition of exactly how treatment start and completion were operationalized.

Interpreting a mean duration requires attention to the spread of individual observations as well as the group averages. The reported standard deviations indicate variation around those averages, but the registry record does not provide the individual outcome distribution. It also does not explain how incomplete or unusually long treatment courses were handled. Consequently, the summary describes the recorded group means and their uncertainty, not every participant's treatment course.

7. Results Posted in the Registry

• Methadone After Phenobarbital for Withdrawal: mean 17.70 versus 19.10 on control; difference -1.40 (95% CI -7.24 to 4.44), standardized effect d = -0.15; z-test p = 0.638.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant's treatment length is measured in days, and the registry record summarizes each group using a mean and standard deviation. A mean describes the central average across observed values. A standard deviation describes how spread out individual values are around that average. These two summaries answer different questions: the group mean describes average duration, while the standard deviation describes participant-level variability.

What does the mean difference represent?

The reported mean difference is -1.4 days, with methadone after phenobarbital compared with dDTO after phenobarbital. The negative sign indicates that the methadone group's posted mean is lower than the comparator group's mean. The comparison is an unadjusted contrast of the group means, rather than an adjusted estimate accounting for other variables. The registry record does not report an adjusted analysis or covariates used in an analysis model.

For a continuous outcome, a difference in means is expressed in the outcome's original units. Here, that unit is days. This makes the estimate directly interpretable as a difference in average treatment duration. However, the estimate alone does not convey its precision. The confidence interval is needed to show how uncertain the estimated contrast is, and the standard deviations give context about variation among participants.

How should the confidence interval be understood?

A confidence interval is a range of values compatible with the observed data under the assumptions of the method used to calculate it. In general, a narrower interval indicates a more precise estimate, whereas a wider interval indicates less precision. The interval for the mean difference is -7.238 to 4.438 days. Since it contains zero, the data do not distinguish clearly between a mean difference favoring either direction and no difference. The interval does not say that individual participants' treatment lengths fall within these endpoints.

The registry-derived comparison also reports an unadjusted p-value of 0.638. In general, a p-value measures how unusual the observed data, or data more extreme, would be under a specified null model. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The registry record does not report a complete analysis plan or identify a sponsor-reported inferential analysis. The posted p-value should therefore be read with the associated estimate and interval, not as a standalone verdict.

Why does variation matter?

There are 20 participants reported in each outcome group. The observed standard deviations are 8.8 days for dDTO after phenobarbital and 10.0 days for methadone after phenobarbital. When participant outcomes vary substantially, a modest difference in group averages can be difficult to estimate precisely, particularly with limited observations. General statistical reasoning expects more variability to increase uncertainty if other design features remain unchanged. This is one reason to consider the confidence interval alongside the group means.

The underlying distribution of treatment durations is not reported in the registry record. A mean and standard deviation alone do not reveal whether values are symmetric, skewed, clustered, or influenced by a small number of longer courses. No distributional plot or participant-level data are available in the registry record, so those features cannot be assessed from the posted summaries.

What is a planning illustration?

The sample-size figures are planning illustrations calculated from the observed effect, not a report of the trial's original design calculation. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is specified as a stated fraction of the observed effect. Smaller effects require more participants to detect under the same assumptions, because they are harder to distinguish from the background variation.

These illustrations are prospective planning quantities: they show participant counts that would be associated with the stated assumptions and target power for a future design. They are not estimates of how likely this completed trial was to detect an effect. The registry record does not report the trial's original sample-size assumptions or justification, so the planning illustrations cannot be treated as a reconstruction of that original decision.

What can and cannot be inferred?

The methods support a comparison of group-average treatment duration as posted. They do not establish equivalence, identify why treatment lengths may differ, or describe outcomes not reported in the registry record. The record does not report whether the analysis followed intention-to-treat principles, how missing values were addressed, or whether any participants were excluded from the outcome analysis. Such details matter because the interpretation of a randomized comparison depends not only on the numerical estimate but also on how participants and outcomes were handled.

More generally, estimates from a trial are interpreted in light of the population enrolled, the interventions compared, the outcome definition, and the conduct and analysis of the study. Here the record identifies the population as infants with NAS, the shared phenobarbital context, and the two opioid medications. It gives a treatment-duration outcome and summary statistics, but many implementation and analysis details are not reported in the registry record. The numerical findings should therefore be understood as a summary of the posted results, with the stated uncertainty and reporting limits.

10. Confidence Intervals and Precision

The estimated mean difference is -1.4 days for methadone after phenobarbital relative to dDTO after phenobarbital. Its confidence interval extends from -7.238 to 4.438 days. The interval includes zero and includes values on either side of zero, so the estimate does not precisely determine the direction or size of the underlying mean difference. The data remain compatible with a difference favoring either group as well as with no mean difference.

The interval is wide in relation to the estimated difference, reflecting substantial uncertainty about the contrast. The observed group standard deviations are 8.8 days and 10.0 days, while the outcome summaries include 20 participants in each group. Variation among participant outcomes, together with the number of observations, contributes to the precision of a mean comparison. The record does not provide participant-level values or additional analysis details that would allow a fuller assessment of the source of uncertainty.

The confidence interval concerns uncertainty in the estimated difference between group means, not the range of treatment durations experienced by individual infants. The standard deviations are the summaries that describe participant-level spread. Neither the interval nor the p-value indicates that the two treatment approaches are equivalent. Demonstrating equivalence would require a defined acceptable range for differences and a suitable prespecified analysis, which are not reported in the registry record.

The unadjusted p-value of 0.638 is consistent with the interval's inclusion of zero, but it does not resolve the uncertainty. The estimate and interval are more informative when read together: the estimate gives the observed direction and magnitude, while the interval indicates that the magnitude remains poorly pinned down by these data.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations, not counts from the completed trial. For this continuous outcome, the listed numbers are participants per arm, not total event counts. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row considers an effect to detect expressed as a fraction of the observed effect. The trial's original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the planned participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect were the true effect and the assumptions held. The 90% power column gives the corresponding participants per arm for a design with a 90% chance. These are design targets, not guarantees about results. The figures are 711 and 952 participants per arm for planning for 100% of the observed effect; 1,264 and 1,692 for planning for 75% of the observed effect; and 2,843 and 3,805 for planning for 50% of the observed effect.

The pattern reflects a general statistical principle: smaller effects are harder to distinguish from random variation, so detecting them with the same target power requires more participants. The curve represents the same planning relationship across effect sizes rather than a separate result from the trial. These figures are not observed power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -1.400; pooled standard deviation σ = 9.419.
2. n = 2 × (1.96 + 0.842)² × 9.419² / -1.400² = 710.6, rounded up to 711 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -1.4                      # observed difference in means
sigma <- 9.41912947145329                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1723722)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 711 (80% power), 952 (90% power)
 75% of observed effect: n per arm = 1,264 (80% power), 1,692 (90% power)
 50% of observed effect: n per arm = 2,843 (80% power), 3,805 (90% power)
power.t.test: 711.5 
Simulated power at n = 711 per arm: 0.804 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and has no secondary outcomes with posted results. Because only one outcome is listed, the record does not present a set of posted outcome tests for which a multiplicity adjustment can be assessed. It does not report a prespecified multiplicity strategy, a hierarchy of outcomes, or any additional analysis plan. The absence of posted secondary results should not be interpreted as evidence that no other outcomes were considered during the study; those details are not reported in the registry record.

The record reports an unadjusted p-value for the mean comparison. It does not describe whether any other analyses were planned or performed, whether alternative outcome definitions were examined, or whether any adjustment was used. Without a protocol or statistical analysis plan in the registry record, the relationship between the posted result and any prespecified testing strategy cannot be evaluated.

Missing-data handling is not reported in the registry record. The posted outcome summaries include 20 participants in each group, but the record does not state whether these numbers represent all randomized participants, whether any participants lacked a treatment-duration measurement, or how incomplete observations were treated. The registry record also does not report the frequency or reasons for withdrawals, exclusions, or missing outcomes.

The analysis population is described for the primary outcome as completion of treatment, but the exact analysis set is not defined. The record does not say whether participants were analyzed according to randomized assignment, according to treatment received, or under another rule. These distinctions can matter in randomized trials, especially if treatment changes, discontinuations, or missing observations occur. They cannot be resolved from the posted summary statistics.

Accordingly, the reported means and comparison should be interpreted as the registry's posted outcome summary. More detailed conclusions about multiplicity control, missing-data assumptions, or analysis populations are not possible from the registry record.

14. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

The adverse-event summary reports zero serious adverse events among 20 participants at risk in the methadone-after-phenobarbital group and zero among 20 participants at risk in the DTO-after-phenobarbital group. It also reports zero other adverse events among the 20 participants at risk in each group. No serious adverse-event terms are listed.

These figures describe the events recorded in the registry summary; they do not establish that no events of any kind occurred outside the categories or reporting period captured by the record. The death fields are not populated, so deaths are not reported in the registry record. The record does not provide event definitions, observation duration for safety, severity details beyond the serious-event category, or information on how adverse events were collected. The counts should therefore be read as posted safety summaries, not as a complete characterization of safety.

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

The posted results show that the group receiving methadone after phenobarbital had a mean opioid-medication treatment length of 17.7 days, while the group receiving dDTO after phenobarbital had a mean of 19.1 days. The registry-derived estimate of the mean difference is -1.4 days for methadone relative to dDTO. The confidence interval, -7.238 to 4.438 days, is broad and includes zero. The unadjusted p-value is 0.638. These data do not provide a precise estimate of the difference in average treatment length.

The result does not prove that the treatment combinations have identical effects, and it does not establish equivalence. It also does not show that one approach is better or worse in clinical terms. The trial's posted primary outcome is treatment duration, and no secondary outcome results are posted. The means and their uncertainty cannot answer questions about outcomes not included in the registry summary.

The comparison concerns two treatment combinations that both include phenobarbital. It therefore does not estimate the effect of phenobarbital alone, nor does it represent a comparison of the opioid medications in the absence of phenobarbital. The registry record also does not provide enough detail about treatment completion rules, participant flow, missing observations, or the analysis population to assess how those factors may affect the reported comparison.

The record identifies a randomized, open-label, parallel-group design, which frames the intended comparison, but the details of randomization and trial conduct are not reported. The findings should be understood as a summary of the enrolled trial's posted treatment-duration data, with uncertainty and limitations in reporting. They are not individualized guidance and do not determine what care should be used in any particular circumstance.

16. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is framed as a direct comparison of average treatment duration between two randomized groups, while the posted estimate is accompanied by substantial uncertainty. The group means differ by a reported -1.4 days in the methadone-relative-to-dDTO comparison, but the confidence interval ranges from -7.238 to 4.438 days. A point estimate alone can look definite; the interval makes clear that the data do not tightly locate the difference.

The example also illustrates why a non-significant result is not the same as evidence of equivalence. The p-value is 0.638, and the interval includes zero, but the interval also allows differences in either direction. Without a prespecified equivalence margin and a suitable analysis, the findings cannot establish that the approaches are sufficiently similar.

Another statistical consideration is variability. The group standard deviations, 8.8 and 10.0 days, indicate notable spread in treatment duration relative to the mean contrast. With 20 participants reported in each outcome group, the uncertainty around the mean comparison remains important to interpretation. The sample-size planning figures further illustrate how the required participants per arm rise when the target effect is smaller, under the stated planning assumptions.

Finally, the registry record demonstrates the importance of reporting the analysis plan and participant handling. Details on missing observations, analysis populations, and original sample-size justification are not reported. Such information helps readers judge whether a numerical result reflects the intended analysis and how broadly it can be interpreted. The posted summaries are informative, but they do not substitute for those design and analysis details.

17. 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 registry record gives limited detail about eligibility criteria, participant characteristics, and the clinical setting beyond identifying infants with Neonatal Abstinence Syndrome. This restricts assessment of how closely the enrolled participants represent other populations. The record identifies randomization but does not describe sequence generation or allocation concealment. Masking is listed as none, and the comparison is open label.

The treatment descriptions are incomplete. They identify the shared use of phenobarbital and the two opioid medications, and they refer to dosing guides linked to NAS scores. However, the complete dosing schedules and the operational rules for stabilization, tapering, and treatment completion are not reported in the registry record. Because the endpoint is duration, those details would help readers understand how the outcome was determined.

The primary endpoint is summarized by group mean and standard deviation, but participant-level results and distributional information are not reported. The record does not explain how missing treatment-duration values, withdrawals, protocol deviations, or treatment changes were handled. It also does not define the analysis population beyond describing the outcome population as completion of treatment.

The registry record does not report the original sample-size calculation, a complete statistical analysis plan, interim analyses, or a prespecified equivalence framework. The planning illustrations based on the observed effect are not a substitute for the trial's own design rationale. Finally, the safety summary does not give event definitions or detailed follow-up information, and deaths are not reported in the registry record. These reporting limits qualify interpretation of both the efficacy summary and the adverse-event figures.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Treatment of Neonatal Abstinence Syndrome — NCT01723722.
• Registry record last updated 2013-11-27; status last verified 2013-11.
• Results first posted 2013-11-27.
• 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.

21. Record Summary

The registry record describes a completed Phase 4 randomized, open-label, parallel-group trial sponsored by Eastern Maine Medical Center. It enrolled 40 participants with Neonatal Abstinence Syndrome. The comparison was phenobarbital with methadone versus phenobarbital with diluted deodorized tincture of opium.

The primary outcome was length of opioid-medication treatment in days, summarized as a mean and standard deviation at completion of treatment. The posted means were 17.7 days for methadone and 19.1 days for dDTO. The registry-derived mean difference was -1.4 days, with a confidence interval from -7.238 to 4.438 and an unadjusted p-value of 0.638. The interval indicates substantial uncertainty about the difference.

The registry record lists no secondary outcome results. It reports zero serious and zero other adverse events in each group; deaths are not reported. Details about the original sample-size rationale, missing-data handling, analysis population, and full statistical plan are not reported in the registry record.