Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Morphine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Morphine (NCT04138615), a randomized phase 1, phase 2 study. The primary outcome is Tolerance to Simulated Hemorrhage.

2. Clinical Question

3. Trial Design

This was a randomized, single-masked crossover trial listed in Phase 1 and Phase 2. It compared intravenous morphine with intravenous saline placebo in a laboratory procedure designed to simulate blood loss. The registry record lists 44 enrolled participants and marks the trial as completed. It reports a start date of 2019-11-12 and a primary completion date of 2022-01-04.

A crossover design exposes participants to more than one treatment condition, allowing each participant to serve as their own comparator when the data are analyzed as paired observations. That feature can account for stable differences between people, but it also makes the treatment sequence and paired analysis important to interpretation. The registry record identifies the crossover model but does not report the treatment order, how assignment sequences were generated, whether a washout interval was used, or how period and sequence effects were handled.

Single masking indicates that the registry classifies the study as masked at one level. The identity of the masked party is not reported in the registry record. The record identifies morphine and placebo as the two interventions and describes saline as the placebo infusion.

The primary outcome is reported for 30 observations under morphine and 30 under placebo. Since the record does not state whether these outcome observations form complete matched pairs, the group counts cannot establish how many paired observations entered an analysis. The difference between enrollment and the outcome counts is not explained. Reasons for any non-inclusion in the reported outcome, and the analysis population used, 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

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 Tolerance to Simulated Hemorrhage, measured over 30 minutes from the onset of applying lower-body negative pressure.

The primary endpoint is tolerance to simulated hemorrhage, quantified with the cumulative stress index (CSI). Participants underwent progressive lower-body negative pressure (LBNP), which the trial description uses to cause progressive central hypovolemia. The challenge continued until symptoms indicating possible syncope, including profound bradycardia, a precipitous fall in arterial blood pressure with narrowing pulse pressure, sustained systolic blood pressure less than 80 mmHg, or subjective symptoms such as light-headedness, sweating, nausea, or dizziness.

The CSI combines the pressure level and duration at each stage of the LBNP challenge, accumulating those contributions until the test ends. The endpoint therefore represents the cumulative exposure tolerated before test termination. In the trial description, a larger CSI represents greater tolerance of the simulated challenge.

This endpoint is used to quantify a laboratory response rather than to measure actual blood loss or a clinical outcome after an injury. The registry lists the timeframe as 30 minutes from the onset of applying LBNP. It reports the CSI as a median with an inter-quartile range. The median is a measure of the center of the observed values, while the inter-quartile range describes the middle portion of their distribution. The registry record does not report a confidence interval for the treatment contrast or an inferential test for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median describe? The median is the value at the center of an ordered set of observations. It is often useful when data are skewed or contain extreme values, because it is less influenced by unusually high or low observations than the arithmetic mean. Here, the primary outcome is explicitly reported as a median for each treatment condition. The registry record does not report the raw CSI observations, so the distribution cannot be inspected beyond the posted summaries.

What does the inter-quartile range describe? The inter-quartile range gives the span from the lower quartile to the upper quartile, covering the middle half of a distribution. The registry reports 251 to 728 for morphine and 473 to 997 for placebo. These ranges describe spread in observed values, not uncertainty about the population median or the contrast between treatments. A confidence interval would address uncertainty in an estimate; none is reported for the primary outcome in the registry record.

Why is crossover structure important? In a crossover trial, measurements under different treatments may be available from the same participant. The within-participant comparison can control for characteristics that remain stable across treatment periods. However, valid estimation and uncertainty depend on preserving the pairing in the analysis. The treatment sequence, period-specific outcome data, and method used to account for repeated measurements are not reported in the registry record. Therefore, the posted group summaries do not show whether the primary contrast was calculated with a paired method or another approach.

General statistical principle: repeated observations from one participant tend to be more alike than observations from unrelated participants. An analysis that accounts for this relationship can estimate uncertainty differently from an analysis that assumes independence. A crossover analysis may also need to consider whether outcomes differ by period or treatment sequence. These are general considerations, not claims about procedures used in this trial; the registry record does not report how these issues were handled.

What can be inferred from the posted summaries? The medians and inter-quartile ranges describe the observed outcome groups. They do not alone provide a treatment-effect estimate with a confidence interval, a test of a null hypothesis, or a measure of statistical significance. The registry record reports zero analyses. No p-value or adjusted estimate is reported, and the primary comparison's inferential method is not reported in the registry record. Without that information, the descriptive values should not be read as a completed test of the trial's primary question.

General statistical principle: a confidence interval communicates the range of effect estimates that are reasonably compatible with the data and the assumptions of an analysis. Its width reflects precision, and its interpretation depends on the model and sampling assumptions. A p-value, when reported, describes how unusual data at least as inconsistent with a specified null model would be under that model. Neither quantity is reported for the primary outcome in the registry record. The posted spread within treatment conditions cannot be used as a replacement for either.

What does the planning information mean? The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The illustrations consider detecting a stated fraction of the observed effect. These are planning assumptions, not evidence about the trial's actual design justification or observed statistical power. The registry record does not report the trial's own sample-size justification or the planned statistical analysis. Any sample-size values derived under those assumptions are illustrations for future planning, not observed power and not additional trial outcomes.

General statistical principle: planning calculations depend on the chosen target effect, variability assumptions, allocation, significance level, and desired power. A planning illustration based on an observed treatment contrast can be sensitive to how that contrast was estimated, particularly when the trial is small or the estimate is imprecise. It should not be interpreted as proof that a trial was adequately powered or that a result is reliable. The registry record does not provide enough detail to assess the original sample-size planning.

Why does the outcome scale matter? The CSI accumulates LBNP level multiplied by time at successive stages, as described in the registry. This produces an outcome that reflects both the challenge intensity and the duration tolerated. Because the endpoint is a cumulative measure and is summarized by medians and inter-quartile ranges, a method designed for means may not automatically be suitable. The record does not report whether a transformation, rank-based test, or other model was used. No method should be attributed to the trial without a registry report.

General statistical principle: over-dispersion occurs when data vary more than a chosen statistical model expects. If present, it can make model-based uncertainty too small unless the analysis accounts for the extra variation. The posted summaries do not establish whether over-dispersion was assessed or whether it was relevant to the analysis. The registry record does not report diagnostics or model assumptions for the primary outcome.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists tolerance to simulated hemorrhage as the primary outcome and pain assessment by algometer as a secondary outcome. It reports two outcome measures and one posted secondary outcome, but zero analyses. No multiplicity adjustment or testing hierarchy is reported in the registry record. When several outcomes or comparisons are tested, the chance of at least one apparently unusual result can increase; statistical plans often address this through prespecified priorities or adjustment methods. This is a general statistical issue, not evidence that any particular method was used in this trial.

Missing-data handling is not reported in the registry record. The primary outcome lists 30 observations under morphine and 30 under placebo, while enrollment is reported as 44. The record does not explain whether all enrolled participants completed both treatment conditions, whether outcome observations were missing, how any missing values were handled, or whether the posted counts represent a particular analysis population. It also does not report whether analyses followed an intention-to-treat principle, a per-protocol approach, or another defined population.

For a crossover comparison, missing data in one period can affect whether a participant contributes a complete paired observation. The registry does not report the number of complete pairs, exclusions, or methods for handling incomplete pairs. These omissions limit assessment of potential bias and precision. No assumptions about the reason for missingness or the analysis population can be inferred from the posted counts alone.

11. 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 0% reporting threshold.

The adverse-event figures are listed separately for the placebo trial and the morphine trial. Each group reports 30 participants at risk for serious adverse events and zero serious adverse events. Each also reports 30 at risk for other adverse events and zero other adverse events. Deaths are reported as zero in both groups. No serious adverse event terms are listed.

These figures describe what was recorded in the trial registry for the listed groups. They should not be interpreted as proving that the treatments carry no risk. A record of zero events in a study does not rule out uncommon events, events that were not detected, or harms that were not included in the posted reporting. The registry record does not provide additional details about adverse-event definitions, surveillance duration, severity grading, or the method used to assess relatedness to treatment.

The adverse-event counts should also be read in the context of the study design and population: this was a randomized crossover laboratory study described as involving healthy participants. The posted figures do not establish safety in other populations or clinical settings. They are a report of observed event counts, not a standalone assessment of comparative safety.

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

The posted results describe a laboratory comparison of morphine and saline placebo during progressive lower-body negative pressure. The primary measure, cumulative stress index, has a median of 385 under morphine and 692 under placebo, with the reported inter-quartile ranges of 251 to 728 and 473 to 997, respectively. These summaries indicate that the observed median was lower in the morphine condition. They do not, on their own, quantify the uncertainty around the difference or establish whether it is statistically distinguishable from chance variation.

The result is specific to the trial's simulated challenge and the population described as healthy. LBNP is used in the protocol description to induce progressive central hypovolemia under controlled laboratory conditions. A response on this endpoint is not the same as an outcome in people experiencing actual hemorrhage, and the registry record does not report patient outcomes or clinical effectiveness measures.

The crossover design makes the within-participant relationship important. The record identifies the design but does not state how the treatment periods were ordered, whether complete paired data were analyzed, or how the statistical analysis handled repeated observations. With zero analyses reported, no inferential result is available in the registry record to support a claim about statistical significance or the precision of a treatment contrast.

Enrollment and outcome counts also need cautious reading. The registry lists 44 enrolled participants and 30 observations for each treatment condition, without explaining the relationship between these figures. It does not report reasons for missing outcomes or the analysis population. Those details matter when assessing how representative the posted outcome data are of all enrolled participants.

The adverse-event record reports zero serious adverse events, zero other adverse events, and zero deaths in each listed group. These counts describe the registry's safety reporting but cannot demonstrate that no risk exists. Overall, the posted record offers descriptive results from a controlled simulation; it does not provide a complete inferential analysis or establish what would occur in clinical use.

13. Why This Trial Matters Statistically

This trial illustrates why the design and the form of outcome reporting must be considered together. A crossover structure can support within-participant comparisons, but interpretation depends on knowing how repeated measurements were linked and analyzed. A pair of group summaries, even when both treatment conditions are reported, does not reveal whether the analysis used that pairing or how it affected uncertainty.

The primary outcome is a cumulative physiological measure rather than a straightforward event count. Its median and inter-quartile range provide a useful description of observed values, but they do not answer the inferential question alone. Readers need an estimate of the treatment contrast and an uncertainty measure to judge its precision. The registry record does not report those results for this outcome.

The trial also highlights the distinction between an enrolled sample and the observations summarized for an outcome. The registry reports 44 enrolled participants and 30 observations under each condition but does not explain the difference or identify the analysis population. In crossover research, whether observations are complete and paired can be especially relevant. Without those details, the descriptive summaries cannot fully convey the data structure.

Finally, the laboratory endpoint addresses a carefully defined simulated challenge. That can make the outcome measurable under controlled conditions, but the resulting evidence remains tied to the population and procedure studied. The record's descriptive findings do not by themselves translate to clinical outcomes or resolve the treatment comparison statistically. These are general lessons in interpreting registry results, not claims about unreported methods or outcomes.

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 result is descriptive: medians and inter-quartile ranges are posted, but the registry reports zero analyses. There is no reported treatment-effect estimate with a confidence interval, no p-value, and no account of the inferential method. Therefore, the precision and statistical significance of the primary comparison cannot be assessed from the registry record.

Although the study is identified as a crossover trial, the registry record does not report the treatment sequence, interval between conditions, or handling of period and sequence effects. It also does not state whether the outcome observations were analyzed as matched pairs or how within-participant correlation was addressed. The number of complete pairs is not reported.

The relationship between 44 enrolled participants and 30 outcome observations per treatment condition is unexplained. Reasons for any missing outcomes, exclusions, or incomplete treatment periods are not reported in the registry record. The analysis population and missing-data methods are also not reported, limiting assessment of potential attrition bias.

The population is described as healthy, and the endpoint is a laboratory simulation using lower-body negative pressure. The registry record does not report patient outcomes under actual hemorrhage or establish whether the findings apply beyond the studied setting. Further population characteristics are not reported in the registry record.

The adverse-event record lists zero events in the categories reported, but the registry does not give further detail on event definitions, monitoring, or relatedness. The record also does not report the trial's own sample-size justification or a statistical analysis plan. These limitations constrain interpretation without changing the descriptive values that are posted.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Analgesics in the Pre-hospital Setting: Implications on Hemorrhage Tolerance - Morphine — NCT04138615.
• Registry record last updated 2023-01-12; status last verified 2022-12.
• Results first posted 2023-01-12.
• 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

The registry record describes a completed randomized, single-masked crossover trial comparing intravenous morphine with intravenous saline placebo during a laboratory simulation of blood loss. The trial is listed in Phase 1 and Phase 2, with 44 participants enrolled. It began on 2019-11-12 and reached primary completion on 2022-01-04.

The primary outcome is cumulative stress index during progressive lower-body negative pressure, reported as a median and inter-quartile range. The posted median is 385 under morphine and 692 under placebo. The registry reports 30 observations for each condition and does not report an inferential analysis of the primary comparison.

A secondary pain assessment using an algometer is listed. Serious adverse events, other adverse events, and deaths are reported as zero in both treatment groups. Details about the treatment sequence, paired analysis, missing data, analysis population, and sample-size justification are not reported in the registry record.