Optimal Dose of Prophylactic Naloxone in Reducing Opioid-Induced Side Effects in Children/Adolescents: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Optimal Dose of Prophylactic Naloxone in Reducing Opioid-Induced Side Effects in Children/Adolescents (NCT00330343), a na phase 2 study. The primary outcome is Number of Participants With Naloxone Side Effects.

2. Clinical Question

The clinical question is therefore about side effects during naloxone infusion in young inpatients receiving morphine, and about dose selection within the stated escalation range. The record describes the goal of finding an optimal prophylactic dose, but its posted primary outcome does not give the observed number of participants affected or show how the outcome varied across doses. It also does not report a control comparison. These omissions prevent the registry information from answering whether any particular dose reduced opioid-induced symptoms, or which dose had the best balance of effects.

3. Trial Design

The registry identifies this as a phase 2, single-group study with no masking. Allocation is listed as not applicable, and the record does not describe a randomized comparison. Naloxone is the listed drug intervention. Its arm description specifies a continuous infusion administered in escalating doses from 0.05 mcg/kg/hr to 1.65 mcg/kg/hour. Participants were to receive intravenous patient-controlled morphine for moderate to severe pain.

The planned population was male and female inpatients older than 6 and younger than 18 years with acute moderate to severe pain. The brief summary says participants would be recruited before intravenous patient-controlled analgesia began; most were expected to be postoperative patients, with treatment and study drug starting in the Post Anesthesia Care Unit or Pediatric Intensive Care Unit. These statements describe the planned setting and population; the registry does not report how many participants met each eligibility characteristic.

The enrollment listed in the record is 75. The brief summary also describes an intention to study between 10 and 99 patients over a 2 year period. The study is marked completed, with a start date of 2004-05 and primary completion listed as 2009-06. These dates and status do not, by themselves, provide information about the conduct of dose escalation, adherence, or completeness of follow-up.

Because the design is single-group and masking is listed as none, the study record does not support interpreting the information as a blinded, randomized comparison with a concurrent control. The registry does not report dose allocation rules, the number of dose levels or cohorts, or whether the escalation proceeded according to a prespecified algorithm. Those design 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

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 Number of Participants With Naloxone Side Effects, measured over 0-48 hours after infusion begins.

The primary outcome is titled as the number of participants with naloxone side effects. Its description identifies incidence of nausea, vomiting, and pruritus following naloxone infusion, and its timeframe is 0-48 hours after infusion begins. The outcome is expressed as participants, with the parameter described as a number and dispersion specified as a 95% confidence interval. This makes the intended endpoint a count of participants experiencing the specified symptoms within the recorded observation window, rather than a measure of symptom intensity or duration.

A participant-level binary outcome can communicate how many people experienced at least one event according to the outcome definition. It is often useful when the clinical concern is whether a symptom occurred at all, though it does not convey how severe or persistent a symptom was. The registry does not clarify whether the primary outcome counted any one of the listed symptoms, each symptom separately, or a particular combination. It also does not describe the assessment schedule or symptom threshold.

Although the outcome is specified, its observed count and confidence interval are not reported in the registry record. No dose-specific primary outcome results are reported either. The posted information therefore identifies what the study intended to measure, but does not quantify the endpoint or show how it changed across the escalating naloxone doses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group dose-finding study and specifies a participant-count endpoint. Understanding what such information can establish requires separating the endpoint definition, the design, and the statistical summaries that would be needed to quantify uncertainty. The record identifies some of these elements, but does not report the primary outcome estimate or the analysis procedures used to obtain it.

What does a participant-count endpoint represent?

The primary outcome is the number of participants with naloxone side effects. The description names nausea, vomiting, and pruritus following infusion, and sets the timeframe at 0-48 hours after infusion begins. In general, a participant-level binary endpoint classifies each person according to whether the defined event occurred during the specified observation window. The count is a summary of those classifications. It does not, by itself, describe symptom severity, how often symptoms recurred, or how long they lasted.

The exact operational definition is important. The registry does not clarify whether a participant was counted if any listed symptom occurred, whether each symptom was assessed separately, or how multiple symptoms in the same participant were handled. It does not report thresholds, assessment instruments, or who assessed symptoms. These details affect how consistently an endpoint can be measured and interpreted, but are not reported in the registry record.

What does a confidence interval add?

The primary outcome lists a 95% confidence interval as its dispersion measure, but the interval itself is not reported. In general, a confidence interval describes the statistical uncertainty around an estimate under the method used to calculate it. It complements the point estimate: a point estimate alone does not show how much uncertainty is associated with the observed data. An interval is not a guarantee that the true value lies within its limits, nor does it address biases or limitations in study conduct.

For a count or proportion based on participant-level events, the interval method matters, particularly when event counts are small or near an endpoint of the possible range. The registry does not identify the calculation method or report the estimate and interval. The precision of the primary endpoint therefore cannot be evaluated from the posted record.

How does the single-group design shape interpretation?

General statistical interpretation of a treatment effect depends on a suitable contrast. A randomized control comparison can help distinguish changes associated with an intervention from changes that might occur for other reasons. This record lists a single-group model and allocation as not applicable, and does not describe a randomized control arm. It therefore does not report a controlled estimate of the effect of naloxone. Even if symptom counts were available, a single-group count alone would describe observations in the study group, not establish what would have happened under a different treatment strategy.

The intervention description states that naloxone was given by continuous infusion in escalating doses from 0.05 mcg/kg/hr to 1.65 mcg/kg/hour. The registry does not report the schedule, assignment criteria, or analysis of those dose steps. Without that information and dose-specific outcome results, no dose-response pattern can be assessed. The record also does not report whether the primary analysis treated dose as a category or as a continuous measure.

What can over-dispersion mean in general?

For count data, a statistical model may assume a particular relationship between the average count and its variability. Over-dispersion occurs when the observed variation is greater than that assumption allows. If it is ignored, standard errors may be too small and confidence intervals too narrow. That general concern is relevant to event-count analyses, but the primary endpoint is described as participants with an event, and no count model is reported. Over-dispersion should not be presumed to have occurred in this study. The registry does not report a model, diagnostic checks, or any adjustment for extra variability.

What do the planning assumptions mean?

The record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. The record also specifies that non-time-to-event planning values are participants per arm. These are planning assumptions, not a report of the study’s own design or evidence of observed power. Their two-arm equal-allocation premise does not match the registry’s description of a single-group study. The registry does not report a trial-specific sample-size justification or power calculation.

In general, a sample-size calculation describes how many participants a future study would plan for under assumed conditions. When based on an effect estimated from observed data, it is sensitive to uncertainty in that estimate. It cannot establish that the completed study had adequate power, and a planning illustration is not a substitute for the actual outcome estimate and its interval. No numerical planning results are reported in the registry record.

What analyses are documented?

The record lists no analysis records. It does not report a statistical model, analysis population, treatment of missing outcome data, adjustment for covariates, or approach to multiple outcomes or dose comparisons. These omissions make it impossible to reconstruct the analysis or assess whether the reported adverse-event counts and the intended primary endpoint were handled in a consistent way. The posted information supports a description of the planned question and some safety counts, but not a full statistical evaluation of the primary question.

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("Naloxone")
n      <- c(64)
events <- c(32)
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  Naloxone  64  32  50.0  37.2  62.8  38.1  61.9  38.1  61.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure, titled as the number of participants with naloxone side effects. Its description includes nausea, vomiting, and pruritus. The record does not explain whether those symptoms were combined into a single endpoint or analyzed as separate outcomes. It also does not report a hierarchy of outcomes, prespecified contrasts among doses, or a multiplicity adjustment. Any plan for controlling the chance of false-positive findings across multiple tests is not reported in the registry record.

The record lists no analysis records. It does not report whether the primary analysis was based on all enrolled participants, participants who began infusion, or another analysis population. The distinction matters because the group included in an analysis determines which participants contribute to the estimate. The registry does not give a participant flow, exclusions, or the number with evaluable primary outcome data. These analysis-population details are not reported in the registry record.

Missing-data handling is also not reported. The record does not say whether symptom assessments were missing, how missing observations were classified, or whether any imputation or sensitivity analysis was used. For an endpoint observed during a defined follow-up period, incomplete assessment can affect the interpretation of the event count. Without the missingness information and analysis method, the potential impact cannot be evaluated.

These gaps do not establish that multiplicity or missing data caused bias. They mean that the registry information is insufficient to determine how these issues were addressed. No conclusion about the robustness of the primary analysis can be made without the analysis plan and results, which are not reported in the registry record.

12. 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.

Most frequent non-serious adverse event terms

The registry’s adverse-event data list Group 1 with 59 participants at risk for serious adverse events and 0 affected. For other adverse events, 59 are listed as at risk and 32 as affected. These are descriptive counts in the registry’s safety record. They are not the primary outcome result, whose stated focus is participants with nausea, vomiting, or pruritus following naloxone infusion.

The record does not report the adverse-event observation period, event definitions, severity criteria, or attribution to naloxone or morphine. It also does not give a confidence interval for these safety counts or describe how events were collected. The serious-event terms list contains no terms, but that does not supply further information about the event definitions or ascertainment process.

A recorded count of 0 serious events is not proof that serious events cannot occur. It describes the events captured in this study record under its unreported collection and follow-up procedures. The count of 32 other adverse-event participants similarly does not establish that the events were caused by the study drug. The registry lists deaths as null, which is not the same as a reported count of zero. Safety interpretation should therefore remain descriptive and bounded by the information recorded.

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

The registry record shows that investigators set out to study prophylactic naloxone in children and adolescents receiving intravenous patient-controlled morphine. It describes a continuous infusion administered in escalating doses from 0.05 mcg/kg/hr to 1.65 mcg/kg/hour, and specifies a primary outcome concerning participants with naloxone side effects during 0-48 hours after infusion begins. It also identifies a single-group, unmasked design.

What the posted information does not show is the primary outcome result. It gives no observed primary count, confidence interval, or comparison of results by dose. The registry therefore does not establish whether symptoms were prevented or minimized, whether the outcome differed at different doses, or which dose should be considered optimal. The term dose-finding describes the study’s purpose, not a result demonstrated by the information in the record.

The adverse-event counts offer limited descriptive safety information: 0 serious adverse events among 59 listed at risk and 32 other adverse-event participants among 59 listed at risk for that category. These counts do not replace the primary endpoint and do not establish cause. The record does not report event timing or definitions, attribution, or a precision estimate for the safety counts.

More generally, a single-group study can describe what was observed among participants who received the study intervention, but a controlled comparison is needed to support a direct estimate of how outcomes differ under another treatment condition. This record does not describe such a comparison. The registry also does not report the analysis plan, missing-data methods, or dose-specific outcome estimates. Those gaps limit conclusions about both treatment effects and the reliability of any dose-response interpretation.

The results should therefore be read as an incomplete registry account of a completed dose-finding study, rather than as evidence for a particular dose or a quantified effect on symptoms. The intended question is clear, but the primary result needed to answer it is not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable because its stated goal is dose finding, while the registry describes a single-group design and does not report the primary outcome result by dose. Dose-finding questions need information about how outcomes vary across doses, not merely a description of the dose range used. Without dose-specific estimates and their uncertainty, readers cannot assess whether the data indicate a pattern or support selecting an optimal dose.

The endpoint also illustrates the difference between defining an outcome and reporting an outcome. The record names a participant-count measure for nausea, vomiting, and pruritus over a defined period, and specifies a confidence interval as the dispersion measure. But without the count and interval, neither the frequency nor the precision is available for evaluation. A clearly stated endpoint does not by itself provide evidence about its observed value.

The registry’s design description matters as well. A single-group study without a reported control comparison can provide observations about the treated group, but does not provide a direct randomized contrast. Statistical interpretation should respect that distinction rather than treating the study as a controlled test of efficacy. The description of escalating infusion doses does not alone tell readers how dose assignment or analysis was conducted.

Finally, the record separates the primary question from a small amount of safety information. The serious and other adverse-event counts are useful as descriptive registry entries, but their definitions and observation period are not reported, and they do not answer the specified primary question. This example underscores why endpoint results, uncertainty estimates, analysis details, and safety context all matter when interpreting a clinical trial record.

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 central limitation is that the primary outcome result is not reported in the registry record. Although the intended endpoint, symptom description, timeframe, and confidence-interval measure are specified, no observed count, interval, or dose-specific estimate is available. The dose-finding objective therefore cannot be assessed from the posted information.

The study is described as single-group, with allocation not applicable and masking none. No randomized control comparison is reported. This limits what can be inferred about differences attributable to naloxone, because the registry does not provide an outcome contrast against a concurrent control condition. The dose-escalation description gives a range but does not explain dose assignment, escalation rules, or how dose was incorporated in analysis.

The primary endpoint definition remains incomplete in the record. It does not specify whether the three listed symptoms were combined, how symptoms were assessed, or how severity and repeated events were handled. The adverse-event section does not supply an observation period, definitions, or attribution details. Its counts cannot fill the gap in the primary outcome reporting.

Analysis information is also limited. The registry lists no analysis records and does not report the analysis population, missing-data procedures, multiplicity strategy, or statistical model. The sample-size assumptions are described as planning illustrations rather than the trial’s own design; the record does not provide a trial-specific justification. The enrollment listed as 75 does not establish how many participants contributed evaluable data to the primary outcome.

These limitations concern what can be determined from the registry information. They should not be taken as evidence that the study did or did not follow a particular unreported procedure. The missing details are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Optimal Dose of Prophylactic Naloxone in Reducing Opioid-Induced Side Effects in Children/Adolescents — NCT00330343.
• Registry record last updated 2017-07-19; status last verified 2017-07.
• Results first posted 2017-07-19.
• 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

NCT00330343 is a completed phase 2 study sponsored by Johns Hopkins University, listed as starting in 2004-05 with primary completion in 2009-06. The registry describes a single-group, unmasked dose-finding study of continuous naloxone infusion in children and adolescents receiving intravenous patient-controlled morphine. The stated infusion range is 0.05 mcg/kg/hr to 1.65 mcg/kg/hour.

The primary outcome concerns the number of participants with nausea, vomiting, or pruritus following naloxone infusion during 0-48 hours after infusion begins. Its result is not reported in the registry record. The safety record lists 0 serious adverse events among 59 at risk and 32 other adverse-event participants among 59 at risk. The registry does not report the analysis details needed to interpret a dose-specific effect or determine an optimal dose.