Fentanyl for Breakthrough Pain in the Emergency Department: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fentanyl for Breakthrough Pain in the Emergency Department (NCT01812759), a randomized phase 4 study. The primary outcome is Number of Participants With Total Pain Relief Score (TOTPAR4) at Four Hours After Treatment Initiation..

2. Clinical Question

The study also set out to examine whether fentanyl nasal spray could reduce emergency department length of stay. That aim appears in the brief summary, but no secondary outcome results are posted. The intended comparison isolates the nasal spray assignment while both groups receive hydromorphone PCA. The record reports enrollment of 3 and a terminated status; it does not state why the trial ended. The small amount of posted outcome information means the clinical question remains unresolved by the registry results. The record does not establish whether the planned outcome could be assessed for participants who received medication.

3. Trial Design

This was a Phase 4 randomized, double-blind, parallel-group trial sponsored by M.D. Anderson Cancer Center. Its official title describes a comparison of fentanyl nasal spray plus hydromorphone demand PCA with placebo nasal spray plus hydromorphone demand PCA for breakthrough cancer pain in the emergency department. The registry identifies pain as the condition. The planned arms therefore shared intravenous hydromorphone PCA and differed in whether the nasal spray contained fentanyl or placebo.

The arm descriptions specify demand dosing with an initial hydromorphone loading dose of 0.2 mg, demand doses of 0.2 mg, and a lockout interval of 15 minutes. The description says there would be no basal dose. These are descriptions of the intended regimen, not evidence that participants received it. The primary outcome population note states that one participant consented but was admitted to hospital before medication was administered.

Enrollment was 3, and the trial status is terminated. The record gives a start date of 2014-01-10 and a primary completion date of 2014-10-22. It does not report the reason for termination, the number randomized to each planned arm, or how many participants received study medication. The outcome entries list placebo, intervention, and no-medication groups; the no-medication entry has a participant count of 0. That outcome categorization does not replace the study’s stated randomized comparison. The registry record does not explain the relationship between those entries and the planned two-arm design.

Randomization and masking describe features of the intended design. They do not by themselves establish that allocation proceeded as planned or that masking was maintained. The record does not report further details about allocation procedures or masking assessment. Given the limited enrollment and absence of an estimable arm comparison, the design information describes the study’s intent rather than furnishing a reliable estimate of the relative outcomes.

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: The first patient's primary physician admitted the patient to the hospital after the patient consented to the study but before the patient received any medication.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One participant consented but admitted to hospital before medication administered

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 Total Pain Relief Score (TOTPAR4) at Four Hours After Treatment Initiation., measured over 4 hours.

The primary endpoint was the number of participants with a total pain relief score (TOTPAR4) at 4 hours after treatment initiation. TOTPAR4 is defined in the record as the sum of hourly pain relief scores from baseline through 4 hours after the first administered dose of Lazanda or placebo. Each hourly score ranges from -1, indicating worse pain, to 4, indicating complete relief. The summed score can range from -4 to 16. A TOTPAR4 score of 8 or higher is defined as a positive response.

This endpoint turns repeated reports of pain relief into a summary over a specified period. In general, a prespecified threshold can make an outcome easier to interpret as a response count, while retaining the underlying score’s information about relief over time. The threshold is part of the endpoint definition; it is not evidence that the trial observed a difference between groups.

The registry lists the endpoint as a participant count and gives the timeframe as 4 hours. It does not post an estimable comparison of the number meeting the response threshold between the fentanyl and placebo groups. The outcome population note also says that one participant consented but was admitted before medication was administered. Consequently, the endpoint definition is clear, but the posted record does not establish how the endpoint results relate to treatment actually received.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a binary primary outcome: whether a participant had a TOTPAR4 score of 8 or higher at 4 hours after treatment initiation. A binary endpoint places each participant into one of two outcome categories, such as meeting or not meeting the stated response criterion. The registry’s outcome is expressed as a count of participants, rather than as a group mean score. It reports no analysis for this endpoint.

Why an arm comparison is needed

The clinical question concerns the difference in response between the fentanyl spray group and the placebo spray group, with hydromorphone PCA planned in both. A count for one group alone cannot show how outcomes compare between assignments. A statistical comparison needs interpretable outcome information for both arms, together with a clear account of which participants contributed to those data. The record explicitly says that values are missing or not estimable for a two-arm comparison of the binary endpoint. It does not provide an effect estimate or an inferential test that can answer the planned question.

What an effect estimate and interval would mean

General statistical explanation: an effect estimate summarizes the observed contrast between groups on a chosen scale. A confidence interval describes uncertainty around that estimate and indicates which effect values remain compatible with the observed data and the assumptions of the method. A narrow interval generally indicates greater precision than a wide interval. An interval that includes no difference does not prove that the groups are identical; it can also reflect limited information. Here, the registry record contains no estimable contrast or confidence interval, so precision cannot be assessed from the posted primary outcome.

What a p-value could and could not show

General statistical explanation: a p-value measures how unusual data at least as incompatible with a specified null model would be if that model and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. A p-value also cannot repair an unclear analysis population or missing outcome information. No p-value is reported for the primary two-arm comparison, and none should be inferred from the group entries.

Why the counts require caution

The primary outcome entries list placebo and intervention counts of 1, with values of 1 for both, while the no-medication entry has a count and value of 0. Separately, the outcome population description says that one participant consented but was admitted before medication was administered. The record does not reconcile these statements or say whether the listed values represent participants meeting the TOTPAR4 response threshold after treatment. Because the endpoint is defined by a score after treatment initiation, clarity about treatment and outcome assessment is important to interpreting a response count. The record does not supply that clarification.

Planning assumptions are not trial results

General statistical explanation: a sample-size calculation describes how many participants a planned study might need under stated assumptions about the effect to detect, significance level, allocation, and statistical method. It is a planning exercise, not a measure of the strength of results actually observed. The registry includes a description of assumptions for a planning illustration based on an observed effect, but it does not report calculated participant requirements in the outcome information. No sample-size justification for the trial’s own design is reported in the registry record. No observed power should be inferred from the enrollment or from the absence of an estimable result.

For binary outcomes, the amount of information depends in part on how many participants have each outcome and how many are observed in each group. When the available counts are sparse or the analysis population is unclear, estimates can be unstable or unavailable under a chosen method. General statistical explanation: methods for sparse binary data may use different assumptions or approaches, but the registry record does not identify an analysis method for this endpoint. It would not be appropriate to select a method after seeing the posted entries and present its result as the sponsor’s analysis.

The record reports no analysis entries, so the method used for any sponsor assessment is not reported in the registry record. It also does not report adjustment variables, an analysis population, or handling of missing primary outcome data. The distinction matters: a statistical method produces an estimate from a defined set of observations, while the registry’s outcome definition alone does not establish which observations were analyzed. In this case the available information supports describing the intended endpoint and the lack of an estimable posted comparison, but not reconstructing an analysis.

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("Placebo", "Intervention")
n      <- c(1, 1)
events <- c(1, 1)
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  Placebo  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7
ARM  Intervention  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and no posted secondary outcome results. The brief summary mentions both pain relief and emergency department length of stay as research aims, but the registry’s outcome information contains only the primary TOTPAR4 measure. A formal multiplicity plan—how the interpretation of statistical tests would account for assessing multiple outcomes or comparisons—is not reported in the registry record. With no posted analyses or p-values, there is no multiplicity adjustment to interpret.

Missing-data handling is also not reported. The primary outcome population note states that one participant consented but was admitted to hospital before medication was administered. The record does not say whether this participant was included in the outcome entries, how treatment exposure was handled, or whether other primary outcome values were unavailable. It does not report an imputation method, a sensitivity analysis, or a rule for classifying participants without an assessed score.

The analysis population is not reported in the registry record. In general, an intention-to-treat analysis groups participants according to randomized assignment, while a treated or per-protocol analysis may use different inclusion rules. Those approaches answer different questions and can produce different estimates. The record does not identify which approach was used, nor does it provide enough information to infer one from the arm counts.

These omissions matter because the endpoint depends on pain-relief scores recorded after treatment initiation, and the population note describes a participant who did not receive medication. Without a stated analysis population and missing-data rules, the meaning of the posted counts cannot be established. The registry record therefore does not permit assessment of multiplicity control, attrition handling, or whether the analyzed population followed the randomized design.

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 5% reporting threshold.

The registry’s safety entries report 0 serious adverse events and 0 deaths in each listed group. For the placebo group and intervention group, the record lists 1 participant at risk for serious adverse events and 1 at risk for other adverse events, with 0 affected in each category. The no-medication group is also listed with 1 at risk for each category and 0 affected, despite its primary outcome entry reporting a participant count of 0. No serious adverse event terms are listed.

These entries are counts, not estimates of comparative safety. The record does not provide a statistical comparison, confidence interval, or explanation of the relationship between the safety group counts and the planned randomized arms. The outcome population note says that one participant was admitted before medication was administered, which adds uncertainty about exposure and inclusion in the safety record.

General statistical explanation: when the number of participants observed is limited, zero recorded events cannot establish that an event cannot occur or that risks are equivalent between groups. The registry entries describe what is posted for the listed groups; they do not support a broader safety conclusion. The reason for termination and the completeness of safety follow-up are not reported in the registry record.

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

The record establishes that a randomized, double-blind, parallel-group study was intended to compare fentanyl nasal spray plus hydromorphone PCA with placebo nasal spray plus hydromorphone PCA for breakthrough cancer pain in the emergency department. It defines a primary response outcome based on TOTPAR4 at 4 hours and identifies a score of 8 or higher as a positive response. Enrollment was 3, and the study is listed as terminated.

What the posted results do not establish is whether fentanyl and placebo differed on that primary outcome. No estimable two-arm comparison, effect estimate, confidence interval, or p-value is reported. The arm entries cannot resolve the question because the record does not explain how they relate to the outcome population note, which describes a participant admitted before medication was administered. The registry also does not post results for the emergency department length-of-stay aim.

General statistical explanation: a lack of an estimable result is different from a finding of no effect. Evidence of no meaningful difference would require a sufficiently informative estimate and an interpretation tied to the range of effects compatible with the data. The registry record provides neither. The absence of posted analysis also does not establish that the trial’s design features were ineffective or that a particular treatment result occurred.

The safety entries report no serious adverse events or deaths in the listed groups, but the small and unclear denominators limit interpretation. Those counts do not show that risk is absent or equal across assignments. Overall, the registry record documents the intended study question and limited outcome information, not a conclusion about the relative effects of the two nasal sprays.

14. Why This Trial Matters Statistically

This trial illustrates why a stated design and a defined endpoint are not enough to answer a clinical question statistically. Randomization and double masking are relevant design features, and the primary outcome is defined with a clear time point and response threshold. But a comparison also requires outcome information that can be assigned unambiguously to the randomized groups and analyzed under a stated approach.

Here, the registry lists enrollment of 3, reports a terminated status, and provides no analysis for the primary outcome. Its stated reason is that values are missing or not estimable for a two-arm comparison of the binary endpoint. The arm entries are difficult to reconcile with the primary outcome population note describing a participant admitted before medication was administered. This makes transparent reporting of participant flow, treatment exposure, and outcome assessment particularly important to interpretation.

General statistical explanation: small studies can be useful for feasibility or exploratory aims, but sparse outcome information often leaves estimates imprecise or prevents a comparison from being estimated at all. A planning calculation cannot replace observed data, and a null or missing result cannot be interpreted as proof of equivalence. The registry’s enrollment and outcome record do not support a quantitative assessment of the intended treatment contrast.

The statistical lesson is to distinguish design intent, outcome definition, and analyzable evidence. The first two are described in the record; the third is not available for the primary comparison. Clear reporting of the analysis population, missing outcome handling, and reasons for stopping would help readers understand what was observed and what remains unknown. Those details are not reported in the registry 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 primary limitation is the absence of an estimable two-arm result for the primary endpoint. The registry reports no analysis, effect estimate, confidence interval, or p-value. It explicitly states that values are missing or not estimable for the binary comparison. Therefore, the posted results cannot quantify the contrast that the randomized design was intended to assess.

Enrollment was 3 and the trial is listed as terminated, but the reason for termination is not reported in the registry record. The number randomized to each planned arm, the number who received medication, and the number with an assessed primary outcome are not clearly reported. The outcome population note says one participant consented but was admitted before medication administration, while arm entries list counts for placebo and intervention. The record does not explain how those entries fit together.

The registry lists a no-medication outcome group with a count of 0, and a safety group at risk of 1. It does not explain these categories or their relation to the stated randomized comparison. No analysis population, missing-data method, sensitivity analysis, or multiplicity plan is reported in the registry record. No secondary results are posted, including for the emergency department length-of-stay aim.

Safety interpretation is limited by the small listed at-risk counts and the absence of information about exposure and follow-up. The record reports no serious adverse events or deaths, but does not permit a robust comparison or broad inference. These limitations concern the available registry information and do not establish what may have been observed outside that record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fentanyl for Breakthrough Pain in the Emergency Department — NCT01812759.
• Registry record last updated 2021-06-29; status last verified 2021-06.
• Results first posted 2020-10-14.
• 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

NCT01812759 is a Phase 4 randomized, double-blind, parallel-group trial sponsored by M.D. Anderson Cancer Center. It was designed to compare fentanyl nasal spray plus intravenous hydromorphone demand PCA with placebo nasal spray plus hydromorphone demand PCA for breakthrough cancer pain in the emergency department. Enrollment was 3; the record lists the trial as terminated.

The primary endpoint was the number of participants with TOTPAR4 at 4 hours after treatment initiation, with a score of 8 or higher defined as a positive response. The registry reports no analyses and says the binary two-arm comparison is not estimable. Its primary outcome population note describes one participant who consented but was admitted before medication administration. The record reports no secondary outcome results and does not state why the trial ended.

Safety entries list 0 serious adverse events and 0 deaths in each group, with limited and unclear at-risk counts. The registry does not provide an interpretable estimate of the primary treatment contrast or a basis for concluding that the groups differed or were equivalent.