Evaluation of Bispectral Index (BIS™) and Levels of Sedation With Common Inhalational Anesthetics in Healthy Volunteers (OLIVER): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Bispectral Index (BIS™) and Levels of Sedation With Common Inhalational Anesthetics in Healthy Volunteers (OLIVER) (NCT04602546), a randomized na study. The primary outcome is BIS 50.

2. Clinical Question

The trial’s stated aim was to examine the relationship between BIS and inhaled anesthetics across a range of anesthetic concentrations and hypnotic states, and to provide evidence about BIS performance with isoflurane, sevoflurane, and desflurane in combination with opioids. The primary endpoint is therefore a measure of the relationship between the monitoring index and observed responsiveness, rather than a direct comparison of clinical outcomes between treatments.

The registry identifies the study as randomized, open-label, and parallel-group. It does not report a formal hypothesis comparing each arm with the control arm, nor does it describe a single primary contrast across the five regimens.

3. Trial Design

OLIVER (NCT04602546) is a completed, randomized, open-label, parallel-group study of BIS and sedation with common inhalational anesthetics in healthy volunteers. The registry lists the study phase as not applicable. The sponsor is Medtronic - MITG. The recorded start date is 2021-02-09, and the primary completion date is 2022-08-26.

The five arms were Sevoflurane Alone, Sevoflurane With Remifentanil Group, Sevoflurane With Fentanyl Group, Desflurane Group, and Isoflurane Group. The intervention listed in the registry is the BIS Complete Monitoring System, a device. The control is Sevoflurane Alone. The registry describes sevoflurane administration in steps in the sevoflurane-alone arm. In the opioid arms, remifentanil or fentanyl was combined with sevoflurane. The descriptions for the desflurane and isoflurane arms state that propofol was used before administration of those volatile agents.

The primary endpoint was assessed during anesthesia administration, for up to 2 hours. Its reported values are means with 95% confidence intervals, and the contributing arm counts are 29.0 for Sevoflurane Alone, 27.0 for Sevoflurane With Remifentanil Group, 29.0 for Sevoflurane With Fentanyl Group, 28.0 for Desflurane Group, and 30.0 for Isoflurane Group. These are endpoint counts; the registry does not explain how they relate to total enrollment.

The registry reports two secondary outcome names, BIS 95 and Prediction Probability (PK), but their results are not reported in the registry record. It also does not report a detailed randomization procedure, allocation concealment, or a fuller account of how participants were assigned to groups.

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

Reasons for not completing this period:

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 BIS 50, measured over duration of anesthesia administration, up to 2 hours.

The primary endpoint, BIS 50, is the BIS value at which 50% of participants are unresponsive at a given drug concentration. BIS is an index score on a scale from 0 to 100, with 0 described as dead and 100 as fully awake and responsive. Responsiveness was assessed with the Modified Observer's Assessment of Alertness and Sedation scale, which ranges from 0, no response to deep stimulus, to 5, fully awake.

The endpoint is used to describe how the monitoring index relates to a defined level of responsiveness while anesthetic concentration changes. A value for BIS 50 is not itself a concentration, a direct measure of anesthetic dose, or a treatment outcome. It identifies the index level associated with the stated response threshold under the study’s assessment approach.

The registry gives a mean BIS 50 and a 95% confidence interval for each arm. Reporting the endpoint by regimen allows readers to see the estimates and their uncertainty separately for sevoflurane alone, sevoflurane combined with either opioid, desflurane, and isoflurane. The registry does not report a separate inferential comparison of these arm estimates, nor does it report the method used to derive BIS 50 from the observations.

The endpoint was collected over the duration of anesthesia administration, up to 2 hours. The posted results should therefore be read as estimates for the trial’s monitored volunteer setting and response definition, not as a general threshold applicable to every setting or patient group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous measure, and the registry identifies its summary as a mean with a 95% confidence interval. General explanation: a mean describes the center of a set of measured values, while a confidence interval describes the uncertainty around the estimated mean under the analysis assumptions. The interval does not show the full range of individual measurements. It also does not, by itself, answer whether two arms differ.

What does the 95% confidence interval convey?

General explanation: a confidence interval is an interval estimate built using a statistical procedure. In repeated use under the procedure’s assumptions, intervals would capture the target quantity at the stated rate. For a particular trial, the interval gives a sense of precision around the reported estimate; it is not a guarantee that the true value lies within that particular interval. The registry provides intervals for the arm means, but does not report the calculation method or any assumptions used to derive them.

The reported endpoint means and intervals are specific to BIS 50, the BIS value corresponding to the defined unresponsiveness threshold at a given drug concentration. They should not be confused with BIS 95, which is listed as a secondary outcome. Results for that secondary outcome are not reported in the registry record. The registry also lists Prediction Probability (PK) as a secondary outcome, without posted results.

Why does the randomized parallel design matter?

General explanation: random allocation can help make groups comparable with respect to factors that might affect outcomes, especially when allocation is implemented as intended. A parallel-group design assigns participants to a regimen and evaluates their outcomes within that group, rather than having every participant receive every regimen. The registry identifies this study as randomized and parallel, but does not report the allocation sequence generation or concealment procedures. It also identifies masking as none, so the study was open-label according to the registry. Details about who knew the assigned regimen and how that knowledge was managed during assessment are not reported in the registry record.

The five regimen-specific estimates describe the arms separately. The registry names Sevoflurane Alone as the control, but does not post a defined contrast or a test comparing the other arms against it. A reader should not interpret the order or spacing of the mean estimates as a statistical test. Formal comparison would require an analysis that specifies the comparison and accounts for the study design and uncertainty.

What does the sample-size planning information mean?

General explanation: a planning calculation estimates the sample size that might be needed under stated design assumptions; it is not evidence about the probability that an observed result is true. The planning assumptions described for this trial use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. Those calculations are planning illustrations based on the observed effect, not the trial’s own design justification and not observed power. The registry record does not report the original sample-size justification.

General explanation: when count data are more variable than a simple statistical model expects, over-dispersion can make standard errors too small if it is ignored. This primary outcome is continuous, and the registry does not state that a count model or an over-dispersion adjustment was used. The registry also does not report the model used to estimate BIS 50, so no model-specific assumptions should be inferred from the summary statistics alone.

What analysis details remain unclear?

The registry lists no posted analyses. It does not report an analysis population, treatment of missing observations, covariate adjustment, handling of repeated observations, or sensitivity analyses. Nor does it describe whether the mean estimates were calculated from individual participant summaries or another analysis unit. These omissions limit how fully the endpoint calculations can be assessed. The reported confidence intervals are useful descriptions of precision, but the record does not provide the analysis details needed to reproduce or independently evaluate them.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies BIS 50 as the primary outcome and lists BIS 95 and Prediction Probability (PK) as secondary outcomes. Results for the secondary outcomes are not reported in the registry record. Although several anesthetic regimens are presented, the record does not state which pairwise or overall comparisons were planned, nor does it identify a primary contrast among arms.

Multiplicity arises when several outcomes or comparisons are tested: the chance of at least one misleading positive result can increase unless the analysis plan accounts for the number and structure of tests. General explanation: methods such as a prespecified testing order or an adjustment to significance thresholds can address this issue, but the registry does not report whether any such method was planned or used. No multiplicity-adjusted results are reported.

The registry lists no analyses. It does not describe how missing observations were handled, whether any participants were excluded from an analysis, or how the analysis population was defined. The endpoint counts are reported by arm, but they do not establish the reasons for those counts or the completeness of outcome data. The registry reports total enrollment of 211; the relationship between this enrollment and the endpoint counts is not explained in the registry record.

It is therefore not possible from the posted information to assess whether missingness could have affected the endpoint estimates, whether all randomized participants were included in the primary analysis, or whether the secondary outcomes were analyzed under a prespecified multiplicity plan. These points are reporting limitations, not evidence that any particular method was or was not used.

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.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for each arm. The serious-event affected count is 0 in Sevoflurane Alone, Sevoflurane With Remifentanil Group, Sevoflurane With Fentanyl Group, Desflurane Group, and Isoflurane Group. The corresponding serious-event counts at risk were 33, 29, 32, 35, and 33. Deaths are reported as 0 in each arm. No top serious-event terms are listed.

These are the serious adverse event figures reported in the registry. They describe the observed record for the groups and counts at risk; they do not establish that serious events cannot occur, and they do not by themselves show that one regimen is safer than another. The registry does not report a comparative safety analysis or provide further detail on event ascertainment in the posted results.

The registry also reports other adverse-event affected counts of 13 for Sevoflurane Alone, 24 for Sevoflurane With Remifentanil Group, 29 for Sevoflurane With Fentanyl Group, 14 for the Desflurane Group, and 18 for the Isoflurane Group. These are separate from the serious-event figures. No statistical comparisons or details about event types are reported in the registry record.

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

The reported results characterize arm-specific BIS 50 estimates during anesthesia administration in healthy volunteers. The means range across the five regimens, and each estimate is accompanied by a 95% confidence interval. This provides descriptive information about the BIS value associated with the study’s specified unresponsiveness threshold in each group, together with an indication of estimation uncertainty.

The results do not establish that one anesthetic regimen is superior to another, or that the BIS 50 estimates differ statistically. The registry does not report comparative tests, p-values, adjusted estimates, or a prespecified contrast. Nor does it define a clinically important difference in BIS 50. The reported values therefore should not be interpreted as proof of a meaningful difference based solely on their numerical ordering.

The record also does not establish how well the findings apply beyond the study population and procedures. The study is described as involving healthy volunteers, and the endpoint was assessed during anesthesia administration for up to 2 hours. The registry does not report patient characteristics or information needed to judge applicability to other settings.

The absence of reported serious adverse events in the listed groups is a descriptive safety finding for this registry record, not proof of absence of risk. Other adverse-event affected counts are reported, but no comparative safety analysis is included. BIS 95 and Prediction Probability (PK) appear as secondary outcomes, but their results are not reported in the registry record.

In short, the posted results provide arm-level estimates for a monitoring-related endpoint and counts for reported adverse events. They do not provide enough analytic detail to support causal or comparative conclusions about differences among regimens, and they should be read within the volunteer study context described by the registry.

13. Why This Trial Matters Statistically

This trial is statistically relevant because its primary endpoint links a continuous monitoring index to a defined behavioral response threshold. BIS 50 summarizes the index value associated with unresponsiveness for each regimen, while the confidence intervals communicate uncertainty around those arm-level means. This framing is different from evaluating a single treatment outcome: it concerns how a measurement relates to a response under different anesthetic conditions.

The study also presents several regimens, including inhaled anesthetics administered alone or with opioids. That creates a need to distinguish descriptive estimates from formal comparisons. The registry reports the arm means and intervals, but does not report tests comparing those estimates or a multiplicity strategy. This is a useful reminder that displaying estimates for multiple groups is not equivalent to establishing statistically significant differences among them.

From a biostatistical perspective, the reporting also highlights why analysis details matter. The registry identifies the design as randomized, open-label, and parallel-group, but does not describe allocation procedures, the model used to estimate BIS 50, missing-data handling, or analysis populations. Those details affect how readers assess the reliability and reproducibility of the estimates.

Finally, the study illustrates the distinction between precision and generalizability. Confidence intervals describe uncertainty in the estimated means under the analysis, but do not resolve whether the volunteer findings apply to other populations or clinical settings. The registry’s endpoint and safety summaries are informative as descriptive results, while the missing comparative and analytic details set clear limits on stronger conclusions.

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 registry record leaves important details about the primary analysis unreported. It gives arm-level means and 95% confidence intervals for BIS 50, but does not describe the statistical model, the method used to estimate the endpoint, or whether repeated measurements were incorporated in the analysis. The record also does not report an analysis population or how missing observations were handled.

Total enrollment is listed as 211, while the endpoint counts are reported separately for the five arms. The record does not explain the relationship between enrollment and those endpoint counts, or whether the endpoint counts reflect exclusions, unavailable measurements, or another reason. No interpretation of that difference can be established from the registry record.

The study is identified as randomized and open-label, but allocation procedures and the practical details of masking are not described. The registry does not report a formal contrast, a comparative test, p-values, covariate adjustment, sensitivity analyses, or a multiplicity approach. Secondary outcomes are named but their results are not reported in the registry record.

The available description also limits assessment of applicability. The title identifies healthy volunteers, while fuller participant characteristics are not reported in the posted results. The endpoint was measured during anesthesia administration for up to 2 hours; the record does not describe the extent to which these estimates generalize to other populations or settings. Safety counts are reported, but event descriptions and comparative safety analyses are not.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of Bispectral Index (BIS™) and Levels of Sedation With Common Inhalational Anesthetics in Healthy Volunteers (OLIVER) — NCT04602546.
• Registry record last updated 2023-04-18; status last verified 2023-03.
• Results first posted 2023-04-18.
• 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

OLIVER (NCT04602546) is a completed, randomized, open-label, parallel-group study sponsored by Medtronic - MITG. The registry lists total enrollment of 211, a start date of 2021-02-09, and a primary completion date of 2022-08-26. The study examined BIS and sedation in healthy volunteers receiving sevoflurane alone, sevoflurane with remifentanil, sevoflurane with fentanyl, desflurane, or isoflurane.

The primary endpoint was BIS 50, reported as a mean with a 95% confidence interval by arm. The registry also lists BIS 95 and Prediction Probability (PK) as secondary outcomes, but their results are not reported in the registry record. Serious adverse event affected counts and deaths are reported as 0 in each arm; other adverse-event affected counts are also listed.

The registry does not report comparative tests, the primary analysis method, missing-data handling, or an analysis population. Its results therefore offer descriptive estimates and safety counts, without a posted inferential comparison among the regimens.