Evaluate Safety of Tramadol in the Management of Postoperative Pain Following Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluate Safety of Tramadol in the Management of Postoperative Pain Following Surgery (NCT03395808), a na phase 3 study. The primary outcome is Adverse Events.

2. Clinical Question

The clinical question is about safety reporting among people receiving intravenous tramadol after surgery. It is not a question about whether tramadol reduces pain compared with another treatment, because the registry record describes one treatment group and no comparator. The primary outcome is adverse events, measured as a count of participants, rather than a comparative estimate of pain relief.

The stated timeframe is up to 21 days. The record does not provide more detail about the precise follow-up schedule, how long each participant was observed, or the criteria used to classify an event. Those details are not reported in the registry record. The posted outcome therefore answers a bounded descriptive question: how many participants in the recorded group had adverse events during the stated observation period.

Safety counts can help describe what was observed during treatment and follow-up, but they do not establish that the treatment caused an event. Without a control group, the record cannot compare event occurrence under tramadol with event occurrence under another treatment or with no treatment. It also does not report a primary pain-effectiveness outcome. Interpretation should stay with the safety information that was recorded, rather than extending it to comparative effectiveness or causal conclusions.

3. Trial Design

The registry record identifies NCT03395808 as a Phase 3, multicenter, single-arm, open-label study. Its title describes an evaluation of tramadol infusion (AVE-901) for postoperative pain following surgery. The intervention is listed as a drug, and the arm is identified as AVE-901 50mg, described as intravenous tramadol. The record lists 251 participants enrolled and gives a completed status.

Single-arm means that the posted design has one treatment group, rather than separate treatment and control groups. The allocation field is listed as not applicable, and the masking field indicates none. In general, an open-label study does not conceal assigned treatment from participants or study personnel. The registry record does not give further operational detail about who knew what, or how outcome assessments were conducted.

The record gives a study start date of 2017-12-22 and a primary completion date of 2019-04-25. The primary outcome is adverse events, expressed as participants with an event, with a timeframe of up to 21 days. The posted safety data identify 251 participants at risk for the serious-event measure and 251 at risk for other adverse events. These denominators describe the posted outcome data; the record does not provide a participant flow account or explain whether all enrolled participants contributed observations for the full timeframe.

The record lists one outcome measure and no statistical analyses. It does not report a protocol-level statistical analysis plan, a sample-size justification, or any interim analyses. Those omissions limit what can be said about the intended statistical procedures. The design supports a description of events in the treated group, but not a like-for-like estimate of the difference between treatments. The study's completed status does not, by itself, supply additional information about the completeness of follow-up or the interpretation of the safety counts.

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 Adverse Events, measured over Up to 21 days.

The primary endpoint is titled “Adverse Events” and is measured as the count of participants with reported adverse events. The timeframe is up to 21 days. The outcome description says “Reported Adverse Events,” and the unit is participants. Thus, the posted measure concerns how many people were recorded as having an event, not the total number of individual event episodes.

Safety outcomes are used to describe unwanted or harmful events observed while people receive an intervention and during the specified observation period. In general, participant counts can communicate how widely an event was reported within the group under observation. They do not, on their own, show that the intervention caused an event. Context such as a control group, event definitions, timing, severity, and participant-level follow-up can be important for interpretation; several of these details are not reported in the registry record.

The posted record separates serious adverse events from other adverse events. It reports 2 participants with serious adverse events among 251 at risk, and 149 participants with other adverse events among 251 at risk. These are descriptive counts. The endpoint does not provide a comparative treatment effect, and the record does not list a separate primary pain-relief measure. The available outcome therefore addresses safety reporting in the observed group, not comparative efficacy or attribution of individual events to tramadol.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome uses participants as its unit. A participant count records how many people had at least one event in the relevant category, rather than how many event episodes occurred. This distinction matters because one person could potentially have multiple events. The record does not explain whether repeated events were counted separately elsewhere, or how events spanning categories were handled. The posted result should therefore be read as a number of participants affected, not as a total event burden.

The serious adverse-event data list 2 participants affected and 251 at risk. The other adverse-event data list 149 participants affected and 251 at risk. The registry record gives these counts directly. No additional rate or comparison is needed to describe them, and no unreported statistic should be inferred from the counts. The safety categories are reported separately; the record does not state that they are exclusive.

Why is a comparator important?

In general, a treatment comparison asks how outcomes differ between groups that received different interventions. A randomized comparison can help distinguish treatment differences from other influences, although its reliability still depends on design, conduct, and analysis. This study is listed as single-group, with no allocation to a control group and no masking. Its safety findings are therefore descriptive of the observed treated group. They cannot estimate a difference in event occurrence between tramadol and a comparator.

Without a comparator, the data also cannot separate events related to treatment from events that could occur after surgery or during the same period for other reasons. This is a limitation of what the design can answer, not a claim that any particular event was or was not caused by treatment. The registry record does not provide information that would allow causal attribution for individual events.

What would uncertainty intervals add?

In general, a confidence interval gives a range of values compatible with the observed data under a specified statistical model and procedure. It helps show how imprecisely a result is estimated; it is not a guarantee that the true value lies in that range. The registry record lists no confidence intervals or other uncertainty estimates for the adverse-event counts. No interval should be inferred from the posted results without making additional assumptions and calculations.

For a single-group safety proportion, an interval would concern the event frequency in a population similar to the study group under the chosen model. It would not solve the lack of a comparator or establish causality. It would also not address possible bias from who enrolled, how events were collected, or whether follow-up was complete. Those issues require design and conduct information, not just a statistical interval.

What can the sample-size assumptions tell a reader?

The registry record includes an illustration based on detecting a stated fraction of an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that non-time-to-event planning results are expressed as participants per arm. These are assumptions for a planning illustration, not evidence that the trial used those design choices. The actual study is single-group, so an illustration built around two arms should not be confused with the trial's observed design or its results.

In general, a planning calculation estimates the amount of information that might be needed to detect a specified effect under stated assumptions. It depends on the assumed effect, error rate, allocation, and statistical model. Such a calculation is not observed power and does not demonstrate that an effect exists. The record does not report the trial's own sample-size justification, and the assumptions for an illustration cannot be treated as the protocol's rationale. No numerical sample-size conclusion is stated.

What analyses are listed?

The registry record lists no statistical analyses. It does not report a formal hypothesis test, adjusted model, confidence interval, or prespecified analysis method for the primary outcome. The event counts can be described, but a statistical result beyond those counts is not available in the record. The absence of a listed analysis does not establish what may have been done outside the registry record; it means those procedures are not reported in the registry record.

In general, a statistical analysis plan specifies how outcomes, populations, missing observations, and multiplicity will be handled. Such details help readers distinguish planned analyses from exploratory ones and understand the assumptions behind estimates. The plan is not reported in the registry record. Consequently, interpretation should remain anchored to the posted descriptive data and should not assume unreported methods, adjustments, or decision rules.

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("IV Tramadol 50 mg")
n      <- c(251)
events <- c(251)
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  IV Tramadol 50 mg  251  251  100.0  98.5  100.0  98.5  100.0  98.5  100.0

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study makes several statistical comparisons or tests. In general, repeated testing can increase the chance of obtaining an apparently notable result by chance, so a protocol may specify how multiple outcomes or analyses will be handled. The registry record lists one outcome measure and no statistical analyses. It does not report a multiplicity adjustment, a testing hierarchy, or a broader prespecified analysis plan. Whether multiplicity was considered in other study materials is not reported in the registry record.

Missing-data handling is also not reported in the registry record. The record gives 251 participants at risk for serious adverse events and 251 at risk for other adverse events, but it does not describe participant flow, losses to follow-up, incomplete event reporting, or how any missing observations were handled. Those denominators alone do not establish that every enrolled participant completed the full observation period or had complete ascertainment.

The record does not define analysis populations, such as whether analyses included all enrolled participants or a subset meeting particular criteria. It does not describe exclusions, protocol deviations, or how participants with incomplete information were treated. These details matter because the population contributing data can affect the meaning of a safety count. They are not reported in the registry record and should not be reconstructed from the totals.

For these reasons, no claim about missing-data bias, multiplicity control, or a particular analysis population can be made from the posted record. The available figures are best treated as reported descriptive counts, with the scope of follow-up and data completeness unresolved.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: post procedural hematoma (0.8%).

The serious adverse-event result is a participant count: 2 participants with serious adverse events among 251 at risk. The record also reports 0 deaths. These figures describe the posted study group; they are not estimates of a treatment difference because no comparator group is listed. The record does not state the seriousness criteria or give enough detail to determine how events were assessed.

“Post procedural hematoma” is listed as the top serious adverse-event term, with 0.8% reported. This term-level percentage should be read as the registry's reported value for that term. The record does not say that the term accounts for every serious event, nor does it provide a detailed account of event timing, severity, outcome, or attribution. The percentage does not establish that tramadol caused the event.

Serious adverse events and other adverse events are separate categories in the posted data. There are 149 participants reported with other adverse events among 251 at risk. The record does not explain overlap between categories, so the counts should not be added or interpreted as a total number of distinct participants with any event. In general, safety counts are most informative when read alongside definitions, collection methods, follow-up completeness, and a suitable comparison. Those details are not reported in the registry record.

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

The posted results establish that adverse events were recorded among participants in the AVE-901 50mg group during a timeframe of up to 21 days. Specifically, 2 participants were reported with serious adverse events among 251 at risk, 149 were reported with other adverse events among 251 at risk, and the record lists 0 deaths. The top serious term is “Post procedural hematoma,” reported as 0.8%. These values describe the registry record; they do not by themselves explain why the events occurred.

The study design does not provide a like-for-like control group. As a result, the posted data do not show whether adverse-event occurrence was higher or lower than it would have been under another intervention or under different care. A single-group count cannot isolate the effect of treatment from surgery, other circumstances, or background event occurrence. The record does not report individual causal assessments.

The data also do not establish comparative effectiveness for postoperative pain. The primary outcome is adverse events, and the registry record lists no pain-relief outcome or statistical analysis. It would be inappropriate to infer an effect on pain from the safety counts. Nor does the absence of a listed death prove that the risk of death is zero; it only reports the count recorded for this group.

In general, a fuller assessment of safety would consider event definitions, collection procedures, timing, severity, follow-up, and an appropriate comparison where available. Several of these details are not reported in the registry record. The reported counts can support a descriptive account of what was posted, but they cannot provide a precise comparative estimate or a causal conclusion. The record should therefore be understood as limited safety reporting for a single treated group, rather than a definitive comparison of treatment risks or benefits.

14. Why This Trial Matters Statistically

This study is statistically notable for the distinction between describing events and estimating comparative effects. The registry record contains safety counts for one treated group, rather than outcomes from randomized treatment and control groups. That design can document what was reported among participants who received the intervention, but it does not estimate how those outcomes would differ under another treatment.

The distinction matters especially for adverse events after surgery. A recorded event can occur during treatment without being caused by the treatment. In general, a comparator helps contextualize event occurrence, while event definitions and collection methods clarify what was counted. The registry record lists neither a comparator nor detailed event-assessment procedures. This limits causal interpretation, even when participant counts and denominators are available.

The record also illustrates the importance of separating endpoint units. The primary measure counts participants with events, not the total number of event episodes. The serious-event and other-event counts answer different descriptive questions, and the registry record does not explain overlap between categories. Treating them as interchangeable or combining them without that information would change the interpretation.

Finally, a completed study and a numerical outcome do not automatically provide a complete statistical account. No statistical analyses are listed, and the record does not report uncertainty intervals, missing-data procedures, or analysis populations. The reported figures are useful as posted descriptions, but their scope is defined by the information actually recorded. Recognizing those boundaries is an important part of responsible interpretation in clinical biostatistics.

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 principal limitation is the single-arm design. There is no control group in the registry record, so the reported event counts cannot be used to estimate a comparative safety effect. The open-label design means masking is listed as none; the record does not describe procedures that might reduce differences in event reporting or assessment.

The registry record does not provide detailed eligibility criteria, participant flow, follow-up completion, or the methods used to collect and classify adverse events. Although the stated timeframe is up to 21 days, the record does not explain each participant's observation duration or how incomplete follow-up was handled. It also does not describe the definition of serious adverse events or whether event reports were independently reviewed.

The outcome is presented as participants with events, without a detailed breakdown of event episodes, timing, severity, or participant-level overlap. The record lists 2 participants with serious adverse events and 149 with other adverse events, but does not state whether a participant could be included in both categories. The top serious term is reported as “Post procedural hematoma,” at 0.8%, without further event-level context.

No statistical analyses, confidence intervals, missing-data procedures, analysis populations, multiplicity approach, or trial-specific sample-size justification are reported in the registry record. Accordingly, precision and the statistical assumptions behind any inferential conclusions cannot be assessed from this record. These limitations restrict the findings to a descriptive account of the posted safety data and prevent conclusions about comparative effects or causation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluate Safety of Tramadol in the Management of Postoperative Pain Following Surgery — NCT03395808.
• Registry record last updated 2021-03-09; status last verified 2019-06.
• Results first posted 2021-03-09.
• 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

NCT03395808 is a completed Phase 3, multicenter, single-arm, open-label study of intravenous tramadol (AVE-901 50mg) for postoperative pain following surgery. The registry record lists 251 participants enrolled, a study start date of 2017-12-22, and a primary completion date of 2019-04-25.

The primary outcome is reported adverse events, measured as participants, over a timeframe of up to 21 days. The record lists 2 participants with serious adverse events among 251 at risk, 149 with other adverse events among 251 at risk, and 0 deaths. “Post procedural hematoma” is the top serious adverse-event term, reported as 0.8%.

No statistical analyses are listed. The single-group design provides descriptive safety counts, not a treatment comparison. Further detail on event definitions, follow-up completeness, missing data, analysis populations, and causal assessment is not reported in the registry record.