Intranasal Fentanyl for Initial Treatment of a Vaso-occlusive Crisis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Intranasal Fentanyl for Initial Treatment of a Vaso-occlusive Crisis (NCT01482091), a randomized phase 4 study. The primary outcome is Change in Pain Score 20 Minutes After Administration of Study Drug.

2. Clinical Question

3. Trial Design

The registry describes a completed, randomized, parallel-group, phase 4 trial with quadruple masking. It compared intranasal fentanyl with intranasal saline in patients with sickle cell disease presenting to a pediatric emergency department with a vaso-occlusive crisis. The stated purpose was to determine whether intranasal fentanyl could decrease pain in this setting.

Enrollment was 124. The registry lists the study start as 2011-12 and primary completion as 2015-02. The posted primary outcome has an analysis count of 25 for intranasal saline and 24 for intranasal fentanyl. Those outcome-specific counts should not be treated as a full account of participant flow: reasons for differences between enrollment and the outcome counts, and the disposition of participants, are not reported in the registry record.

The primary endpoint was the change in pain score between baseline and 20 minutes after study drug administration, using the Wong Baker FACES pain scale. The registry reports medians and inter-quartile ranges for the groups, with a Wilcoxon (Mann-Whitney) comparison. Other posted outcomes include adverse effects, admission, emergency-department length of stay, narcotic use, timing of study drug administration, and additional pain-score changes. Not all listed outcomes have posted numerical results in the record.

The record does not report the details of the masking procedures, the allocation sequence, the method used to conceal allocation, or the trial's sample-size justification. It also does not report a complete statistical analysis plan or a description of which analysis population was used.

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: 124 subjects were consented for the study. The study drug was only administered one time in the ED if subjects met all inclusion and exclusion criteria when they arrived with a VOC. Only 49 of the 124 consented subjects received the study drug.

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 Change in Pain Score 20 Minutes After Administration of Study Drug, measured over Baseline and 20 minutes after administration of study drug.

The primary endpoint is the change in pain score from baseline to 20 minutes after administration of the study drug. Pain was assessed with the Wong Baker FACES pain scale, which the registry describes as having six faces representing increasing pain severity, with scores from 0 to 10. The outcome was calculated by subtracting the 20-minute score from the baseline score. Under that definition, a larger positive change represents a greater decrease in pain; a negative change represents an increase.

Using change between measurements gives a concise way to describe how a participant's score moved over the specified interval. It focuses on movement from baseline rather than on the follow-up score alone. The registry reports this endpoint as a median with an inter-quartile range, a summary that describes the middle of the observed distribution and its spread without requiring the values to follow a normal distribution.

The interval is clinically tied to initial emergency-department treatment: it assesses pain-score change shortly after the study drug was administered. The registry record does not report why this particular time point was selected, the scale's assessment procedures, or how missing baseline or follow-up scores were handled. The primary result therefore describes the recorded change at the specified assessment time, not the full course of pain during the emergency-department visit or after discharge.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is summarized with a median and inter-quartile range, and the groups are compared using the Wilcoxon (Mann-Whitney) method. These choices describe the center and spread of the observed scores and test whether the distributions differ without relying on the same assumptions as a conventional comparison of means.

What does the median describe?

The median is the middle value when observations are ordered. It is less affected by unusually high or low observations than the mean. The inter-quartile range runs from the first to the third quartile and describes the spread of the middle half of the observations. Neither statistic, alone, gives a confidence interval for the population value. Here, the reported medians and inter-quartile ranges are descriptive summaries of the change scores in each group.

What does the Wilcoxon (Mann-Whitney) test assess?

In general, this rank-based test compares the relative ordering of observations in two independent groups. It is often used when a normal-distribution model for the raw measurements is not suitable or when a rank-based comparison is preferred. It does not directly test a difference between medians under every possible distribution shape. If the group distributions differ in spread or shape, a test result can reflect more than a simple shift in their medians. The registry record names the method but does not report additional assumptions, diagnostics, or a detailed test specification.

How should the p-value be read?

In general, a p-value describes how compatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it is not a measure of the size of the effect. The reported primary p-value is p = 0.048. The registry does not report a confidence interval for the primary comparison, so the precision of the between-group effect is not expressed directly as an interval.

What do confidence intervals add?

In general, a confidence interval gives a range of effect values compatible with the data and the method used to construct it. Its width conveys precision: broader intervals indicate greater uncertainty. A confidence interval should be interpreted with its assumptions and the selected confidence level in mind. No confidence interval is reported for the primary endpoint. Confidence intervals reported for some secondary comparisons are recalculated from posted summary statistics and are unadjusted; they should not be confused with intervals reported by the trial investigators.

Why can over-dispersion matter?

In general, over-dispersion occurs when data vary more than a statistical model expects. If a model assumes less variability than is present, standard errors may be too small and tests may appear more decisive than warranted. The primary endpoint is analyzed with a rank-based method rather than a count model, so over-dispersion is not the central issue for that comparison. It can matter for other kinds of outcomes when their analysis relies on a model for counts or event rates. The registry record does not report enough modeling detail to assess whether over-dispersion was evaluated for other endpoints.

What do the planning illustrations represent?

General planning calculations use an assumed effect, variability, significance level, allocation, and target power to illustrate the scale of a future study. They are not estimates of the power achieved by the completed trial. The registry record's planning illustrations are based on observed effects and specify a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is a stated fraction of the observed effect. The record says that the displayed quantities are participants per arm except for time-to-event illustrations, which use total events. These are illustrations, not the trial's original sample-size justification, which is not reported in the registry record.

The registry does not report a full prespecified analysis plan, procedures for missing outcomes, or the handling of protocol deviations. Those omissions limit independent assessment of whether the posted analysis followed the original plan.

10. Analyses Reported by the Sponsor

For the primary endpoint, the registry reports the sponsor's Wilcoxon (Mann-Whitney) analysis with p = 0.048. The descriptive medians and inter-quartile ranges give the observed change-score summaries for each group; the registry does not provide a sponsor-reported confidence interval for the primary comparison. No independent recalculation of that primary test is posted in the record.

For some secondary outcomes, unadjusted recalculations from the posted group summaries are available alongside the sponsor's reported tests. These calculations are simple comparisons based on the available summary data and may not reproduce every feature of the original analysis, such as its handling of missing data or any prespecified analysis choices. For the headache outcome, the sponsor's Fisher Exact result is reported as p = 0.05, while the unadjusted recalculation is p = 0.037. For admission, the sponsor reports p > 0.05 and the unadjusted recalculation is p = 0.484. For time to study drug administration, the sponsor reports p = 0.68 and the unadjusted recalculation is p = 0.663.

These differences should be read in context rather than as evidence that one analysis is incorrect. The record does not report a discrepancy flag, and the sponsor's own analysis remains the study's reported analysis. Recalculations are useful checks on the posted summaries, but they do not replace the original analysis or establish that all analytic choices match.

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists secondary outcomes, but a complete multiplicity plan is not reported in the registry record. In particular, it does not report whether secondary endpoints were tested under a prespecified hierarchy, whether p-values were adjusted, or how the family of comparisons was defined. Without that information, secondary p-values should be treated as unadjusted unless the record explicitly says otherwise. Repeated testing across outcomes can increase the chance that at least one result appears notable by chance; this is a general statistical concern, not proof that any particular finding is spurious.

Missing-data methods are not reported in the registry record. The record does not explain how participants without a baseline or follow-up pain score were handled, whether missingness was assessed, or whether any imputation or sensitivity analyses were used. It also does not give a full account of participant flow or reasons that outcome-specific counts may differ across measures. These omissions limit assessment of whether the analyzed observations represent the randomized groups in a way that preserves the intended comparison.

The analysis population is not reported in the registry record. It is therefore unclear whether the results use an intention-to-treat population, a per-protocol population, or another defined set of participants. The record does not state how crossovers, treatment deviations, or eligibility issues were handled. These details matter because exclusions or changes after randomization can affect comparability between groups.

The record names the primary statistical test, but it does not provide a full statistical analysis plan or report whether the test was selected before results were examined. The trial's sample-size justification and any interim analyses are not reported in the registry record. These gaps prevent a complete assessment of the prespecified inferential framework and should be kept in mind when interpreting the reported p-values.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypoxia (12.5%), hypotension (8.3%).

The registry reports serious adverse events affecting 2 participants in the intranasal saline group and 5 in the intranasal fentanyl group. The corresponding groups at risk are reported as 25 and 24. These are descriptive event counts in the posted record; they do not, by themselves, establish that the study drug caused an event or explain its clinical severity, timing, or relationship to treatment.

Hypoxia and hypotension are listed as the top serious adverse event terms, with reported percentages of 12.5% and 8.3%, respectively. The record does not specify the group attribution for these listed terms in the information available, so the percentages should not be assigned to either treatment group. Death counts are not reported in the registry record.

Other adverse events are also recorded, but counts alone do not provide a complete safety comparison. The registry record does not report detailed event narratives, event timing, causality assessments, or a statistical comparison of serious adverse events. The safety figures should therefore be read as descriptive reporting, not as a standalone estimate of comparative risk.

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

The primary endpoint records pain-score change over the interval from baseline to 20 minutes after study drug administration. The observed median change was larger in the intranasal fentanyl group than in the intranasal saline group, in the direction the registry defines as a greater decrease in pain. The reported Wilcoxon comparison had p = 0.048. These findings describe the observed trial results for this endpoint and time point.

They do not establish the size of a precise population effect: the registry does not report a confidence interval for the primary comparison. A p-value does not say how likely a treatment is to help an individual, nor does it describe the probability that the observed pattern will recur. The study result is also not a guarantee that a similar difference would appear in other patient groups, settings, or treatment conditions.

The primary result does not answer every question about the emergency-department course. Separate outcomes address adverse events, admission, timing, and other measures, and those results should be considered on their own terms. The record's incomplete information about participant flow, missing data, analysis populations, multiplicity, and the statistical plan limits how fully the results can be evaluated.

Accordingly, the posted evidence supports a cautious statement about a difference in the recorded primary pain-score outcome in this randomized comparison. It should not be turned into a broader claim about all outcomes, individual response, or safety. The registry record is one source of trial results, and its level of detail constrains the conclusions that can be drawn from it.

14. Why This Trial Matters Statistically

This trial illustrates why the choice and definition of an endpoint matter. The primary measure is not simply a pain score at follow-up: it is a change score, with the direction of subtraction explicitly defining which values indicate greater decreases or increases in pain. Without that definition, the meaning of a positive or negative change could easily be misread.

It also shows why a test result should be read together with descriptive summaries. The Wilcoxon (Mann-Whitney) p-value addresses a group comparison, while the medians and inter-quartile ranges convey the observed center and spread. Neither element alone gives a complete account of the effect's size and precision. The absence of a confidence interval for the primary comparison leaves uncertainty about the plausible range of the between-group effect less directly characterized.

Finally, a randomized design does not eliminate the need for transparent reporting. Details about participant flow, missing outcomes, analysis populations, multiplicity, and the original analysis plan help readers assess how well the reported estimate represents the intended comparison. The record's secondary outcomes and safety counts add context, but they do not substitute for those methodological details or for a clearly specified primary analysis.

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.

Several trial-specific details needed for a fuller interpretation are not reported in the registry record. The primary endpoint has outcome counts for each group, but the record does not provide a full participant-flow account or explain why counts vary across posted outcomes. It does not describe how missing pain assessments were handled, or whether the analysis included all randomized participants.

The registry does not report a complete protocol or statistical analysis plan, including the rationale for the 20-minute primary assessment, the sample-size justification, interim analyses, or a prespecified hierarchy for secondary outcomes. It names the primary test but does not provide a confidence interval for the primary comparison. These limitations restrict assessment of the estimate's precision and of how closely the posted analysis follows the original plan.

The record describes the trial as quadruple masked, but does not specify which roles were masked or how masking was implemented. It also does not report detailed dosing information in the posted material. The randomized, placebo-controlled design is relevant context, but these unreported details make it difficult to assess implementation from the registry record alone.

Safety reporting is also limited: serious adverse event counts are available, but detailed event narratives, timing, causal assessments, and group attribution for the listed serious-event terms are not reported in the record. These limitations do not show that bias or reporting problems occurred; they mark what cannot be evaluated using the registry information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Intranasal Fentanyl for Initial Treatment of a Vaso-occlusive Crisis — NCT01482091.
• Registry record last updated 2016-08-19; status last verified 2016-07.
• Results first posted 2016-08-19.
• 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

The registry describes a completed, randomized, quadruple-masked, parallel-group phase 4 trial of intranasal fentanyl versus intranasal saline for patients with sickle cell disease presenting with vaso-occlusive crisis pain to a pediatric emergency department. Enrollment was 124. The primary endpoint was change in Wong Baker FACES pain score from baseline to 20 minutes after study drug administration.

The median change was 1.0 units for saline and 2.0 units for fentanyl, with respective inter-quartile ranges of 0.0 to 2.0 and 0.5 to 4.0. The registry reports a Wilcoxon (Mann-Whitney) comparison with p = 0.048. The primary comparison has no reported confidence interval. Secondary outcomes and serious adverse event counts add context, but several methodological details, including missing-data handling, analysis populations, multiplicity procedures, and the sample-size justification, are not reported in the registry record.