Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients (NCT01284140), a randomized na study. The primary outcome is Circadian Timing.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group trial with no masking. The registry lists an enrollment of 24 and a completed status. The trial began in 2011-01, and primary completion was recorded as 2016-12. The phase is listed as NA. Further details about the allocation procedure, the allocation ratio, recruitment, and masking of outcome assessment are not reported in the registry record.

Participants were assigned to a sleep promotion protocol or usual care. The active protocol was behavioral and lasted 48 hours, with timed light exposure as part of sleep and circadian rhythm promotion. The comparator was 48 hours of usual care, also described as behavioral. Further operational details about either arm are not reported in the registry record.

The primary endpoint uses measurements from Day 1 and Day 3 and applies only to subjects with 24-hour 6-sulfatoxymelatonin excretion profiles on both days. The posted arm summaries include 6 participants in the sleep promotion protocol group and 5 in usual care. The registry record does not explain the relationship between these endpoint counts and the enrollment of 24, or report why other enrolled participants are not represented in these arm summaries.

Four secondary outcomes are listed: normal circadian timing, circadian amplitude, spectral edge frequency 95%, and delirium. The record lists 5 outcome measures and 4 analyses. Details about the analysis populations, the order in which outcomes were assessed, and the rationale for the trial size are not reported in the registry record. The design establishes a randomized comparison, but the posted endpoint information is limited to small arm-specific summaries and separate arm-level analyses.

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Before assignment: Two subjects who acutely developed exclusion criteria were withdrawn from the study after enrollment and prior to the performance of any study-related procedures. These subjects were not analyzed.

Randomization and Intervention

Subjects With Paired 24hr Collections

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Subjects with 24-hour 6-sulfatoxymelatonin excretion profiles from both Day 1 and Day 3.

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.

Population: Subjects with 24-hour urinary 6-sulfatoxymelatonin profiles from both Day 1 and Day 3 were analyzed (11 subjects out of a total of 22). One of the remaining subjects had an unevaluable profile from Day 1. The remaining subjects died or had their urinary catheter removed prior to Day 3.

6. Primary Endpoint

The registry lists the primary outcome as Circadian Timing, measured over Day 1 to Day 3.

The primary endpoint is circadian timing, expressed in hours. It measures the magnitude of the phase change in 6-sulfatoxymelatonin excretion between Day 1 and Day 3. For each participant, the timing of the best-fit maximum on Day 1 is compared with the timing of the best-fit maximum on Day 3. A positive result denotes a phase advance: the maximum occurs earlier on Day 3. A negative result denotes a phase delay: the maximum occurs later on Day 3.

This measure is used to characterize a change in circadian timing over the intervention period. It is not a direct measure of sleep duration or sleep quality. The registry record defines the endpoint population as subjects with 24-hour excretion profiles on both measurement days, so the summary pertains to those with the required measurements, rather than necessarily everyone enrolled.

The posted summaries are 3.6 hours for the sleep promotion protocol arm and -2.4 hours for usual care. The record does not post a standard deviation, standard error, or confidence interval for either arm, nor a single between-arm estimate with a confidence interval. The endpoint description says the groups will be compared, but the posted information does not supply a direct estimate of that comparison. The reason this biomarker-based timing measure was selected over other possible circadian measures is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization assigns participants to study groups by chance and is intended to support a fair comparison of outcomes between those groups. The registry identifies this trial as randomized and parallel, but does not report the randomization procedure, allocation concealment, or the allocation ratio. Without those details, readers can recognize the intended randomized design but cannot assess all safeguards against predictable assignment from the registry record alone.

What does the primary endpoint represent?

The endpoint is a change score: it compares the timing of the best-fit maximum in 6-sulfatoxymelatonin excretion between Day 1 and Day 3. Its sign carries directional meaning. Positive values denote a phase advance and negative values denote a phase delay. This lets the arm summaries describe not only the amount of timing change, but also its direction. The endpoint is defined in hours and is restricted to subjects with 24-hour profiles from both days.

A change score is not the same as a direct comparison of randomized arms. The group-level comparison generally needs to estimate how the outcome differs by assignment, together with uncertainty. The posted values of 3.6 and -2.4 are arm summaries. The record does not post a direct contrast, its standard error, or a confidence interval. Thus, no conclusion about the precision of the between-arm estimate can be drawn from a direct contrast in the registry record.

How should the reported F tests be read?

An F test compares model fit or variation under specified statistical models. An extra sum-of-squares F test commonly evaluates whether adding model terms accounts for additional variation relative to a simpler model. The precise model specification and the hypothesis tested are not reported in the registry record. Here, each posted analysis is associated with one group rather than with both randomized groups together. The listed p-values, 0.007 and 0.37, therefore should be interpreted as results of the reported group-specific analyses, not as a test of the randomized treatment contrast.

A p-value describes how compatible the observed data are with a specified statistical null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not quantify the size or clinical importance of an effect. Without the model details and the tested null hypotheses, the scope of these particular p-values cannot be reconstructed from the registry record. They cannot replace an effect estimate with an uncertainty interval for the between-arm comparison.

Why does variability matter?

A mean gives a location summary, while a measure of variability describes how widely individual observations are distributed. The record does not report a spread measure for either arm. General statistical principle: variability affects how precisely an estimated mean or group contrast can be determined. When individual responses vary considerably, the same number of participants can yield less precise estimates than when responses are closely clustered. No variability measure or participant-level data are posted for this endpoint, so the precision cannot be independently assessed from the arm summaries.

General statistical principle: over-dispersion occurs when observed variability is greater than a model assumes. If present, standard errors and uncertainty estimates from a model that assumes less variability may be too small. The registry record does not report an over-dispersion assessment or enough statistical detail to determine whether this issue was considered. This is a general consideration, not a claim that over-dispersion occurred in this trial.

What can planning illustrations establish?

Planning sample sizes are assumptions-based illustrations of the number of participants that might be needed to detect a specified effect under stated statistical conditions. The planning assumptions described for this record use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Such calculations are not observed power and do not measure the probability that the completed trial found a true effect. The registry record does not report the trial's own sample-size justification. The primary outcome is not reduced to a single comparison in the posted recalculation information, so no two-arm planning estimate for that outcome is available there. For outcomes other than time-to-event outcomes, the planning convention is participants per arm; time-to-event planning quantities refer to total events.

Confidence intervals, when reported, communicate the uncertainty around an estimate over a range of values. A narrow interval indicates greater precision than a wide interval, subject to the model assumptions. No interval is posted for the primary between-arm effect. General statistical principle: a non-significant p-value does not establish that there is no effect, just as a small p-value does not by itself establish that an effect is large or important. In this record, the key limitation is that the listed tests are arm-specific and the comparative estimate and its precision are not reported.

10. Analyses Reported by the Sponsor

The registry reports two extra sum-of-squares F tests, one associated with each arm. The p-value for the sleep promotion protocol group is 0.007, and the p-value for usual care is 0.37. The record does not provide the model specification or the exact null hypothesis for either test. Because the analyses are listed separately by group, neither is a direct test of the difference between the randomized arms.

No sponsor-reported between-arm estimate, confidence interval, or comparative p-value for the primary endpoint appears in the registry record. The posted arm summaries, 3.6 hours and -2.4 hours, do not include a measure of spread, so an unadjusted recalculation of the comparison is not available from the posted summary statistics. The registry record's reported analyses therefore remain the available sponsor analyses, while the comparative effect and its precision cannot be assessed from a recalculation.

The record does not flag a discrepancy between a sponsor analysis and a recalculation. Accordingly, there is no conflict to resolve between two estimates. The group-specific p-values should not be substituted for a treatment contrast, and the direction of the arm means should not be interpreted as a complete estimate of the comparative effect.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including the primary circadian timing endpoint and four secondary outcomes: normal circadian timing, circadian amplitude, spectral edge frequency 95%, and delirium. It also lists 4 analyses. The statistical plan for handling multiple outcomes or multiple tests is not reported in the registry record. In particular, the record does not specify whether any adjustment for multiple comparisons was planned, whether outcomes were ordered hierarchically, or which analyses were considered confirmatory.

General statistical principle: testing multiple outcomes or hypotheses can increase the chance of observing at least one apparently notable result by chance. Procedures for multiplicity can control that risk, but the choice depends on the study aims and analysis plan. Without the planned approach and a clear mapping of analyses to outcomes and hypotheses, the listed p-values cannot be evaluated in the context of a multiplicity strategy. This does not establish that adjustment was or was not done; it means the approach is not reported in the registry record.

The registry record defines the primary endpoint population as subjects with 24-hour 6-sulfatoxymelatonin profiles on both Day 1 and Day 3. It reports endpoint summaries for 6 participants in the intervention group and 5 in usual care, compared with enrollment of 24 overall. The reason for the difference between these counts is not reported in the registry record. Missing-data handling, the number of participants lacking either measurement, and whether any imputation was used are also not reported in the registry record.

The analysis population is not described in enough detail to determine whether the endpoint summaries follow an intention-to-treat approach, a per-protocol approach, or another rule. The record does not say how participants with incomplete profiles were handled or whether the group summaries include all randomized participants with available outcome data. General statistical principle: analyses based only on participants with complete measurements can be affected if the availability of measurements is related to outcomes or group assignment. No claim can be made about whether that occurred.

The record also does not report interim analyses, stopping rules, or a detailed statistical analysis plan. Those omissions limit assessment of when and how the hypotheses were tested, but do not demonstrate that a particular procedure was used or omitted during trial conduct.

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 0% reporting threshold.

The registry reports zero serious adverse events among 11 participants at risk in the sleep promotion protocol group and zero among 11 at risk in usual care. It also reports zero other adverse events among 11 at risk in each group. Deaths are reported for 4 participants in the sleep promotion protocol group and 2 in usual care.

These counts describe the adverse-event figures recorded in the registry; they do not establish whether events were related to an intervention. The registry record does not provide event descriptions, timing, causes of death, or a causal assessment. It also does not explain how the adverse-event populations relate to the enrollment of 24 or to the primary endpoint groups of 6 and 5. The adverse-event denominators should therefore be read as the reported at-risk counts for those summaries, not assumed to be the same analysis population as the primary endpoint.

Zero reported serious or other adverse events in these group summaries does not establish that no events occurred outside the recorded categories or period. The registry record does not report additional detail needed to assess completeness of adverse-event ascertainment, severity grading, or attribution. The death counts are presented separately and should not be combined with the adverse-event counts or assigned a cause based on this record.

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

The registry record shows that the mean circadian timing change was 3.6 hours in the sleep promotion protocol group and -2.4 hours in usual care among the participants represented in the primary endpoint summaries. By the endpoint definition, these values correspond to an advance in the intervention group and a delay in usual care. The summaries come from 6 and 5 participants, respectively, with 24-hour profiles on both measurement days.

These findings do not provide a direct estimate of how much the randomized groups differed, or how precisely that difference was estimated. The record reports two separate group-level F tests, but not a comparative confidence interval or a between-arm p-value. The group-specific p-values cannot answer the question of whether the arms differ. In particular, comparing one p-value with another is not a statistical test of the difference between groups.

The endpoint concerns the timing of a biomarker maximum, not a direct measure of sleep duration, sleep quality, delirium, or other clinical outcomes. Although the registry lists secondary outcomes, their results are not reported in the record summarized by these registry entries. The stated study goal concerns practical strategies for sleep and circadian rhythm promotion, but the posted primary endpoint information alone does not address every aspect of that goal.

The results also do not establish whether the endpoint subset represents all enrolled participants. The registry lists enrollment of 24, while the primary summaries include 6 and 5 participants; reasons for the difference and the handling of missing measurements are not reported. No causal interpretation of deaths or adverse events is supported by the posted safety figures alone.

Overall, the registry provides directional arm summaries but limited comparative and precision information. It supports describing the recorded values and their endpoint-defined direction. It does not support a firm conclusion about the size or precision of a randomized treatment contrast, or a broader conclusion about clinical benefit or harm.

14. Why This Trial Matters Statistically

This trial illustrates why the estimand—the precise effect a study aims to estimate—matters. The endpoint description says the changes in the two groups will be compared, but the posted results include arm-specific means and separate arm-level tests rather than a single comparative estimate. Readers need to distinguish those quantities: the summaries describe each group, while the primary randomized question concerns the contrast between groups.

It also illustrates why direction and uncertainty should be considered together. The sign of a circadian timing value has an explicit interpretation: positive values indicate an advance and negative values a delay. But a directional summary alone does not show how much participant-level variation there was, or how precisely the randomized contrast was estimated. The missing spread measures and comparative interval leave those questions unresolved.

The difference between overall enrollment and the endpoint sample counts is another important statistical issue. A result based on participants with measurements from both days may not describe everyone assigned to a group if measurement availability is selective. The registry record does not explain the difference or describe missing-data handling, so readers cannot assess the potential effect of incomplete endpoint data.

Finally, the record demonstrates that a small p-value for one arm and a different p-value for another do not establish a difference between arms. A direct randomized comparison is needed for that question. General statistical principle: transparent reporting of the target contrast, uncertainty, analysis population, and multiplicity strategy allows readers to judge what an analysis establishes and what remains uncertain. Those elements are not fully reported for this primary endpoint.

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 registry record has limited detail for evaluating the primary comparison. It provides arm means and sample sizes, but does not report a variability measure, a direct between-arm estimate, or a confidence interval. The two reported p-values are tied to separate arm-specific F tests. Their precise hypotheses and model specifications are not reported in the registry record, and they do not supply the missing randomized contrast.

The primary endpoint summaries include 6 participants in the sleep promotion protocol group and 5 in usual care, while enrollment is listed as 24. The record does not explain why fewer participants contribute to these summaries, identify the number or reasons for missing profiles, or state how incomplete measurements were handled. It also does not identify the analysis population as intention-to-treat or another defined population.

The registry describes randomization, parallel assignment, and no masking, but further details about allocation, outcome-assessment masking, and the conduct of usual care are not reported in the registry record. The rationale for the enrollment target and the trial's own sample-size justification are also not reported. The record does not provide a detailed statistical analysis plan, an approach to multiplicity, or information about interim analyses.

The reported safety counts include deaths, but do not give causes, timing, event descriptions, or attribution. The relationship between the adverse-event at-risk counts and the primary endpoint population is not explained. These limitations restrict interpretation of both efficacy-related comparisons and safety summaries. They do not prove that any particular design or analysis safeguard was absent; they indicate that the relevant details are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients — NCT01284140.
• Registry record last updated 2018-05-07; status last verified 2018-05.
• Results first posted 2018-05-07.
• 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

NCT01284140, titled “Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients,” is listed as a completed, randomized, parallel-group trial with no masking and an enrollment of 24. The intervention was 48 hours of behavioral sleep and circadian rhythm promotion, including timed light exposure; the comparator was 48 hours of usual care.

The primary outcome was change in 6-sulfatoxymelatonin timing between Day 1 and Day 3, expressed in hours. Posted means were 3.6 for the sleep promotion protocol group and -2.4 for usual care, based on 6 and 5 participants. Separate F-test p-values were 0.007 and 0.37, respectively; a direct between-arm estimate and confidence interval are not reported.

The registry lists four secondary outcomes and reports adverse-event counts, including deaths. Details about missing measurements, analysis populations, multiplicity, and the trial's sample-size rationale are not reported in the registry record.