Open Label Crossover Study Pharmacokinetics (PK) Study in Healthy Volunteers Receiving Various Forms of Fentanyl: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label Crossover Study Pharmacokinetics (PK) Study in Healthy Volunteers Receiving Various Forms of Fentanyl (NCT02470390), a randomized phase 4 study. The primary outcome is Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3).

2. Clinical Question

3. Trial Design

The registry describes an open-label, single-dose, three-way crossover study of fentanyl delivered intranasally, sublingually, and intravenously. It lists randomized allocation and a crossover model, while the brief summary further describes the study as partially randomized. The study was conducted at a single center in healthy volunteers and was designed to assess systemic and CSF pharmacokinetics and bioavailability.

The nasal and sublingual doses were each 200 μg. The nasal dose was given as one 100 μg spray in each nostril, completed within one minute. The sublingual dose was given as a single spray under the tongue. Either route was administered on study day 1 or 3 according to protocol and randomization. The intravenous dose was 100 μg in 2 mL, given over 1-3 minutes on study day 5. The primary endpoint described in the record compares nasal and sublingual fentanyl, not the intravenous arm.

The registry lists 13 participants enrolled and the study status as completed. The listed start and primary completion dates are 2014-11 and 2015-01. The record does not report the sequence allocation details, washout interval, or rationale for the partly randomized schedule. It also does not report a statistical analysis plan or a sample-size justification. These design details should not be inferred from the crossover label alone.

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: A total of 13 healthy subjects were randomly assigned to treatment in this crossover study: 6 in the "Nasal Fentanyl First, then Sublingual Fentanyl and IV Fentanyl" arm and 7 in the "Sublingual Fentanyl First, then Nasal Fentanyl and IV Fentanyl" arm.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions.

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 Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3), measured over 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3).

The primary endpoint is time to reach maximum observed fentanyl concentration in CSF, abbreviated Tmax. It is reported in hours as a median with a full range. The recorded sampling schedule included pre-dose and post-dose CSF measurements over 6 hrs: pre-dose, 5, 10, 20, 30, 45, and 60 min, and 2, 3, 4, and 6 hrs on study days 1 and 3.

Tmax is a timing measure. It identifies when the highest measured concentration occurred among the scheduled observations; it does not measure the size of that concentration. In general, pharmacokinetic studies use timing endpoints to describe how concentration changes over time after administration. Because measurements occur at specified sampling times, the observed Tmax is tied to that schedule and may not identify the exact biological time of a true peak between samples.

The posted median Tmax was 1.01 h for nasal fentanyl, with a full range of 0.75 to 3.0, and 2.0 h for sublingual fentanyl, with a full range of 0.75 to 3.0. These are descriptive summaries for the CSF pharmacokinetic population. The registry does not report a formal estimate of the between-route difference or an inferential test for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is summarized using the median and full range. General explanation: the median is the middle value when observations are ordered, so it describes a central point without requiring the distribution to be symmetric. The full range gives the smallest and largest recorded values. It is easy to interpret, but it does not describe the density of observations within that interval and can be sensitive to extreme values. The registry does not report a standard deviation, interquartile range, or other measure of spread for this endpoint.

Why describe the median?

General explanation: pharmacokinetic timing measures can be skewed, and a median can be a useful descriptive summary when a symmetric distribution should not be assumed. The record specifies median and full range, but does not report why that summary was selected or whether the distribution was assessed. The two medians should therefore be read as summaries, not as a complete description of either route's data.

What does the crossover design change?

General explanation: in a crossover study, participants receive more than one intervention, so a comparison can use within-participant information. Such a comparison can account for stable differences between participants, but it must also consider treatment sequence, period effects, and possible carryover. The registry identifies a crossover model and says the nasal and sublingual interventions were scheduled on study day 1 or 3 per protocol and randomization. It does not report the analysis model, sequence-specific results, or how period and carryover effects were handled. The posted group medians and ranges do not preserve the paired observations needed to reconstruct a within-participant contrast.

How should the sampling schedule be understood?

CSF was scheduled for assessment pre-dose and at 5, 10, 20, 30, 45, and 60 min, and 2, 3, 4, and 6 hrs post-dose on study days 1 and 3. General explanation: observed Tmax depends in part on the times at which samples are collected. If a concentration peak occurs between scheduled samples, the observed maximum may be assigned to a neighboring sampling time rather than the exact time of the peak. The registry reports the schedule but does not describe interpolation or other methods for estimating a peak between observations.

What can be said about statistical uncertainty?

A confidence interval is a range of values compatible with the data and a specified statistical procedure; it communicates precision rather than guaranteeing that a particular value is true. General explanation: paired analysis and confidence intervals can help quantify uncertainty in a crossover treatment contrast. No confidence interval, standard error, test statistic, or p-value is reported for this primary endpoint. The displayed medians and ranges do not permit those quantities to be recovered without additional participant-level information and an analysis method.

How do the planning assumptions fit?

The registry's planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial's own design justification. The numerical planning illustrations and the effect fractions are not reported in the registry record. Any sample-size values presented as planning illustrations should not be interpreted as observed power or as evidence that the trial was adequately powered for this endpoint.

The record lists no posted analyses. It therefore does not specify whether the primary comparison used a parametric or nonparametric test, whether any adjustment was applied, or how participant-level repeated measurements were modeled. General statistical principles can explain why those choices matter, but the method actually used cannot be inferred from a median and range alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and no posted secondary results. The primary outcome entry is one of three listed Tmax outcomes, and its stated comparison is nasal versus sublingual fentanyl. The record does not describe a multiplicity adjustment, a hierarchy among endpoints, or a plan for controlling the chance of false-positive findings across multiple comparisons. It also does not report a prespecified statistical analysis plan. Because no inferential analyses are posted for this endpoint, the record does not show whether multiplicity was addressed in analysis.

The stated CSF pharmacokinetic population includes participants who completed all study periods and had a pre-dose Cmax less than 5%. The endpoint summaries include 10 participants for nasal fentanyl and 9 for sublingual fentanyl. Overall enrollment was 13. The registry does not report participant flow by reason, the number screened or excluded, or why the endpoint group counts differ. It does not describe imputation, sensitivity analyses, or other procedures for missing observations.

General explanation: restricting an analysis to participants with complete periods and a qualifying pre-dose value can make the analyzed population differ from all enrolled participants. In crossover studies, missing data in one period can also affect whether a participant contributes to a paired comparison. The record defines the population but does not explain how these issues were handled beyond that definition. No additional missing-data method should be assumed.

Since only descriptive endpoint summaries are posted, the record does not allow assessment of the consequences of missing data or multiplicity for an inferential conclusion. It also does not report whether analyses were planned for all enrolled participants, participants who received treatment, or another analysis population.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: post lumbar puncture syndrome (7.7%).

The registry reports serious adverse events among 12 participants at risk in the nasal fentanyl group, 13 in the sublingual fentanyl group, and 12 in the intravenous fentanyl group. The corresponding numbers affected were 0, 1, and 0. The listed top serious adverse event term is Post Lumbar Puncture Syndrome, reported as 7.7%. The record does not provide further detail about event timing, severity grades, or attribution to a study intervention.

These are event counts for the groups as reported in the registry, not comparative risk estimates. The groups arise within a crossover study, and the at-risk counts are not a basis for treating the arms as independent parallel groups. The record does not report a statistical comparison of serious adverse events, so the counts do not establish a difference between routes.

For other adverse events, the registry reports 2 affected among 12 at risk for nasal fentanyl, 6 among 13 for sublingual fentanyl, and 0 among 12 for intravenous fentanyl. These counts are distinct from the serious-event counts. Deaths are not reported in the registry record; a missing death value should not be read as a confirmed zero. Adverse-event counts in this small healthy-volunteer study provide a limited description of recorded events and do not establish safety in other populations or settings.

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

The posted primary endpoint describes the observed timing of maximum fentanyl concentration in CSF after nasal and sublingual administration. Median Tmax was 1.01 h for nasal fentanyl and 2.0 h for sublingual fentanyl; both full ranges were 0.75 to 3.0. The summaries apply to the CSF pharmacokinetic population described in the registry, not necessarily to every enrolled participant.

The result does not provide a formal estimate of the route comparison, a confidence interval, or a hypothesis test. It therefore does not show how precisely the route-specific medians or any between-route contrast are estimated. The overlapping ranges are descriptive and do not substitute for an analysis of paired participant-level data. A reader cannot determine from these summaries alone whether the observed difference in medians is compatible with sampling variation under a particular statistical model.

The endpoint concerns a concentration-timing measure in CSF. It is not a measure of pain relief, other clinical outcomes, or patient experience. The registry record does not report a clinical efficacy endpoint in the results, and it does not establish that a route is clinically preferable. No treatment recommendation follows from these pharmacokinetic summaries.

The findings are also specific to the study population and conditions described: healthy volunteers in an open-label crossover study. The record does not establish whether the timing summaries apply to people with illness or to different clinical circumstances. Although the study included intravenous fentanyl, the stated primary endpoint comparison is nasal versus sublingual administration. The posted primary result should not be extended to a comparison involving intravenous fentanyl.

In short, the record gives descriptive evidence about observed CSF Tmax under the study's dosing and sampling schedule. It does not supply the inferential detail, clinical outcomes, or broader population evidence needed to support conclusions beyond that narrow description.

13. Why This Trial Matters Statistically

This trial illustrates why the design and reporting structure matter when interpreting pharmacokinetic results. A crossover design can make within-participant comparisons possible, while a summary consisting only of group medians and ranges does not show those paired data. Without the participant-level contrasts or a reported crossover analysis, readers cannot assess how much of the observed route-specific difference reflects within-person changes versus differences in who contributed to each summary.

The scheduled CSF measurements also shape the endpoint. Tmax is the time of the maximum observed concentration, and the sampling schedule determines the possible observed times. Reporting the schedule alongside the outcome helps readers understand that the measure is tied to those observations, rather than necessarily representing a continuously measured peak time.

The record demonstrates the distinction between descriptive and inferential reporting. Medians and ranges describe the observed data, but they do not quantify uncertainty in a treatment contrast. No confidence interval or inferential test is reported, and no posted analyses are listed. This makes it important not to turn a numerical difference between medians into a claim about statistical certainty.

Finally, the study enrolled 13 healthy volunteers, while the CSF pharmacokinetic endpoint summaries include 10 participants for nasal fentanyl and 9 for sublingual fentanyl. The population definition and group counts are relevant to understanding who contributed to the result. The reasons for the differing counts are not reported in the registry record. Together, these features make the study useful as an example of how a pharmacokinetic result can be narrowly informative while leaving key questions about precision, analysis, and generalizability unanswered.

14. 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 endpoint summaries are limited to medians and full ranges. The registry does not report participant-level observations, a paired route contrast, confidence intervals, standard errors, or a hypothesis test. The statistical model and analysis procedure are not reported in the registry record, so the inferential properties of the comparison cannot be assessed.

The CSF pharmacokinetic population is defined by completion of all study periods and a pre-dose Cmax less than 5%. The endpoint groups contain 10 participants for nasal fentanyl and 9 for sublingual fentanyl, compared with 13 enrolled overall. Reasons for exclusions or incomplete endpoint data are not reported in the registry record. The handling of missing values beyond the stated population definition is also not reported.

The open-label design means masking was none. The record does not explain whether the Tmax assessment could be influenced by knowledge of treatment, nor does it report any safeguards relevant to that possibility. The study is described as partially randomized, but details about sequence assignment and allocation implementation are not reported in the registry record. Washout details and methods for assessing period or carryover effects are also not reported.

The study involved healthy volunteers at a single center, which limits how far its descriptive pharmacokinetic findings can be generalized. The primary endpoint is a CSF timing measure and does not itself describe clinical benefit. The registry lists adverse-event counts but does not provide detailed event narratives or a comparative safety analysis. These limitations constrain interpretation to the posted pharmacokinetic summaries and recorded event counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open Label Crossover Study Pharmacokinetics (PK) Study in Healthy Volunteers Receiving Various Forms of Fentanyl — NCT02470390.
• Registry record last updated 2018-03-16; status last verified 2018-03.
• Results first posted 2018-03-16.
• 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.

18. Record Summary

NCT02470390 is a completed, Phase 4, open-label, single-center crossover study in healthy volunteers. The registry lists randomized allocation, describes the study as partially randomized, and reports enrollment of 13. It compared fentanyl delivered intranasally, sublingually, and intravenously for systemic and CSF pharmacokinetics and bioavailability.

The primary endpoint is CSF Tmax for nasal versus sublingual fentanyl. Median Tmax was 1.01 h (full range 0.75 to 3.0) for nasal fentanyl, with 10 participants, and 2.0 h (full range 0.75 to 3.0) for sublingual fentanyl, with 9 participants. The registry does not report a formal inferential comparison or confidence interval. Serious adverse events were recorded in 0 of 12 at risk for nasal, 1 of 13 for sublingual, and 0 of 12 for intravenous fentanyl. The record does not report deaths.