Treatment of Insomnia in Elderly Sleep Apnea Patients With Ramelteon (TAK 375): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Insomnia in Elderly Sleep Apnea Patients With Ramelteon (TAK 375) (NCT01048242), a randomized phase 3 study. The primary outcome is Sleep Onset Latency.

2. Clinical Question

The trial asked whether ramelteon could improve insomnia in older adults who also had obstructive sleep apnea. Its primary question concerned sleep-onset latency: the study hypothesis was that latency would be lower with ramelteon than with placebo. A secondary objective was to examine whether CPAP compliance improved with ramelteon, on the proposed rationale that reduced insomnia during CPAP use might support compliance.

The intervention was ramelteon 8 mg taken orally before bedtime. The comparator was a sugar pill. The registry describes the conditions as insomnia and obstructive sleep apnea and identifies the intended population as older adults with both conditions. Specific eligibility criteria, including an age threshold, are not reported in the registry record.

The posted primary endpoint is sleep-onset latency, measured in minutes by polysomnography over four weeks. The reported outcome analysis is per protocol. The registry lists mean latency of 9.7 minutes for the ramelteon group and 34.4 minutes for the sugar-pill group. Those are group summaries, not by themselves an estimate of uncertainty or a test of the treatment comparison.

The registry lists CPAP compliance as a secondary study objective, but no secondary outcome results are posted. The primary question can therefore be described from the available data, while the secondary question cannot be answered from the posted results. The record does not report an inferential comparison for sleep-onset latency, such as a confidence interval or p-value.

3. Trial Design

The registry identifies this as a Phase 3, randomized, quadruple-masked, parallel-group trial sponsored by the University of Pennsylvania. Its status is completed. The listed start was 2006-07, and primary completion was 2009-03. Enrollment is recorded as 27. The registry does not report how the randomization sequence was generated, how allocation was concealed, or which parties were masked; the masking label alone does not identify them.

Participants were assigned to ramelteon or a sugar pill. The ramelteon arm description specifies 8 mg orally before bedtime. The primary outcome was assessed over four weeks. The registry describes the outcome population as per protocol, rather than identifying the posted result as an analysis of everyone randomized.

The primary-outcome summaries list 8 participants in the ramelteon group and 13 in the sugar-pill group. These are the analysis counts associated with the posted outcome, not a replacement for the registry’s enrollment figure. The record does not explain why the outcome analysis counts differ from enrollment, nor does it describe participant flow, exclusions, or the reasons any participants may not have contributed to that analysis.

Design details that would help assess conduct—including eligibility criteria, site count, treatment adherence procedures, the randomization method, and the identities of masked groups—are not reported in the registry record. The record also does not state whether any interim analyses were planned or performed. These omissions limit how fully the trial’s conduct and the role of its design choices can be assessed from the registry entry.

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:

Analysis population for the primary outcome, as defined in the registry: analysis per protocol

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 Sleep Onset Latency, measured over 4 weeks.

The primary endpoint is sleep-onset latency, measured in minutes. It represents the time from the start of a sleep assessment to sleep onset; the registry specifies that it was determined by polysomnography. The assessment timeframe is four weeks, and the reported summary measure is the mean with standard deviation.

Sleep-onset latency is used as a direct measure of the insomnia outcome named in the trial objective. A shorter latency corresponds descriptively to less time to fall asleep during the assessment. The registry’s stated hypothesis was that latency would be reduced in the ramelteon group relative to placebo. This framing identifies the intended direction of comparison; it does not establish that a difference was statistically reliable or caused by treatment.

In the per-protocol summaries, the ramelteon group has a mean of 9.7 minutes and a standard deviation of 10.3, while the sugar-pill group has a mean of 34.4 minutes and a standard deviation of 30.7. The standard deviation describes variation among observations around each group’s mean; it is not the uncertainty of the estimated mean or of the between-group contrast. No confidence interval for the contrast is reported.

Because latency is a continuous measure, the group means offer a concise description of the observed outcome, while the standard deviations convey participant-level spread. Interpretation of a treatment comparison also depends on the analysis method, missing-data handling, and uncertainty estimates, which are not reported for this result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous primary outcome summarized by a mean and standard deviation. Understanding what these summaries convey helps distinguish the observed group descriptions from a treatment-effect estimate. It also clarifies why a mean comparison cannot, on its own, show how precise or statistically compatible the result is with a range of possible effects.

What does the mean describe?

For a continuous measure such as sleep-onset latency, the mean is the arithmetic average of the observations included in the analysis. It gives a central summary in the outcome’s units—in this case, minutes. The posted means are 9.7 minutes for ramelteon and 34.4 minutes for the sugar pill. A group mean does not show every participant’s value, and it can be influenced by unusually high or low observations.

What does the standard deviation describe?

The standard deviation describes how dispersed individual observations are around their group mean. It is expressed in the same units as the outcome. The registry reports standard deviations of 10.3 and 30.7, respectively. These measures describe variability among analyzed observations. They are not standard errors, confidence limits, or estimates of the between-group treatment effect. Greater dispersion can make a group mean less precise, but precision also depends on the number of observations and the analysis method.

Why is uncertainty important?

General statistical explanation: an estimate is a summary of data, while an uncertainty interval conveys a range of values compatible with the analysis and its assumptions. A confidence interval is one common way to express that uncertainty. It is useful because it indicates both the direction and the precision of an estimated contrast; a point estimate alone does not. The registry record does not report a confidence interval for the primary comparison. It also does not report a p-value, so the statistical significance of the comparison cannot be assessed from the posted results.

A p-value, in general, describes how compatible observed data are with a specified null hypothesis under the assumptions of a statistical model. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. Since no p-value or formal analysis result is posted, no such interpretation can be made for this trial’s primary endpoint.

What is the role of the analysis population?

The primary outcome population is identified as per protocol. In general, a per-protocol analysis concerns participants who meet protocol-defined conditions for inclusion in that analysis. The exact conditions used in this trial are not reported in the registry record. Nor does the record provide an intention-to-treat result for comparison. Different analysis populations can answer different questions and can be affected differently by exclusions, adherence, and missing outcomes; the population definition and participant flow matter when interpreting a trial estimate.

The posted outcome counts are 8 for ramelteon and 13 for the sugar pill. They should be read as analysis counts attached to the outcome, not as a complete account of enrollment. Enrollment is recorded as 27, but the registry does not explain the difference between enrollment and the outcome analysis counts. It does not state whether missing outcomes, eligibility after randomization, protocol deviations, or another reason accounts for the difference.

Why is a recalculated comparison unavailable?

A simple unadjusted recalculation can sometimes be made from group summaries when the necessary comparison information is available. In this record, the continuous two-arm comparison is identified as not estimable from the available values, and no analysis result is posted. There is therefore no recalculated contrast or uncertainty estimate to interpret. The absence of such a calculation does not show that the groups were the same; it means that the registry information does not support that calculation.

How should planning assumptions be read?

General statistical explanation: a sample-size planning calculation asks how many participants might be needed under specified assumptions to detect a target effect at a chosen significance level and power. It is a design illustration, not a result observed in the trial, and it is not observed power. The planning assumptions recorded for this trial include a two-sided significance level of 0.05, equal allocation, a normal approximation, and target effects expressed as fractions of the observed effect. Those assumptions do not, by themselves, provide the resulting participant counts or establish the trial’s original design rationale. Any sample-size illustration based on the observed effect should be interpreted as planning context, not evidence that the trial was adequately powered.

The registry does not report the original sample-size justification, a prespecified statistical analysis plan, or the model used for the primary outcome. It also does not report whether adjustment for baseline measures or other covariates was planned. These details cannot be inferred from the mean and standard deviation summaries or from the stated planning assumptions.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Ramelteon", "Sugar Pill")
n   <- c(8, 13)
m   <- c(9.7, 34.4)
sp  <- c(10.3, 30.7)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Ramelteon  8  9.700  10.300  1.089  18.311
CARM  Sugar Pill  13  34.400  30.700  15.848  52.952

11. Multiplicity, Missing Data and Analysis Populations

The trial summary describes a primary objective involving sleep-onset latency and a secondary objective involving CPAP compliance. The registry posts one outcome measure and no secondary outcome results. Although CPAP compliance is described as a secondary objective, its measurement definition, timeframe, and results are not reported in the registry record.

Multiplicity arises when an analysis examines multiple outcomes, comparisons, time points, or subgroups, because repeated testing can affect the chance of a false-positive finding. The registry does not report a multiplicity adjustment, a hierarchy of tests, or a statistical analysis plan explaining how the primary and secondary objectives would be handled together. Since no secondary results or inferential primary result are posted, the effect of any multiplicity strategy cannot be assessed.

The primary endpoint is reported for a per-protocol population. The record does not define the per-protocol criteria, report an intention-to-treat analysis, or describe how participants were handled if they did not adhere to treatment or complete the assessment. It also does not report the amount or pattern of missing outcome data, reasons for missingness, or any imputation method. These omissions make it difficult to assess whether the analyzed participants represent the randomized groups and how missing information may have influenced the summaries.

The outcome analysis counts are 8 for ramelteon and 13 for the sugar pill, while the recorded enrollment is 27. The registry does not explain the difference. No participant-flow details are posted that would identify exclusions, withdrawals, or the availability of outcome measurements. These are limitations of the registry information; they do not establish why the counts differ or what impact that had on the result.

12. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events for 0 of 8 participants at risk in the ramelteon group and 0 of 13 participants at risk in the sugar-pill group. These figures indicate that no serious adverse events are recorded among the participants at risk in either listed group. They do not establish the absence of all harms, and the record does not provide additional detail about how events were collected or classified.

Other adverse events are listed for 4 of 8 participants at risk in the ramelteon group and 2 of 13 participants at risk in the sugar-pill group. These are participant counts, not event counts; the registry does not give event-level descriptions in this summary. The record lists no serious adverse-event terms. Deaths are not reported in the registry record.

These safety figures are descriptive. The group counts differ, and no inferential comparison or uncertainty estimate for adverse events is posted. The figures should not be read as demonstrating that one treatment is safer, or that either treatment is free of risk. They describe only the adverse-event information recorded for the listed groups.

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

The primary outcome summaries show that mean sleep-onset latency was 9.7 minutes in the ramelteon group and 34.4 minutes in the sugar-pill group at the four-week assessment. The direction of these observed means matches the trial’s stated hypothesis of lower latency with ramelteon. The standard deviations—10.3 and 30.7, respectively—show substantial spread in the measured values, especially in the sugar-pill group relative to its mean. The registry does not report an inferential comparison or confidence interval, so the precision of the group contrast is unknown.

These results do not establish that ramelteon caused the observed group pattern. Randomization is part of the trial design, but the posted endpoint is per protocol, and the registry does not explain analysis exclusions or missing outcomes. Without those details and an analysis estimate with its uncertainty, the summaries alone cannot show how robust the contrast is to the analysis population or other analytic choices.

The results also do not answer the secondary question about CPAP compliance: no secondary outcome results are posted. The four-week timeframe does not establish what happened beyond that assessment. The record does not provide results for other sleep outcomes, subgroup comparisons, or longer-term follow-up.

The safest interpretation is limited and descriptive. The per-protocol group means are in the direction anticipated by the trial’s hypothesis, but the registry record does not provide the statistical evidence needed to judge the precision or inferential strength of that comparison. Absence of a posted analysis is not evidence that there was no effect; it is a limit on what can be concluded from the record.

14. Why This Trial Matters Statistically

This trial illustrates why a registry entry’s descriptive outcome summaries should be separated from a formal estimate of treatment effect. The primary outcome is clinically interpretable as time to sleep onset, and the means are reported in minutes. Yet means alone do not show the uncertainty around a between-group comparison. The standard deviations add information about participant-level variation but cannot substitute for a confidence interval or an analysis result.

The record also highlights the importance of knowing which participants contributed to a reported analysis. The trial lists enrollment as 27, while the primary outcome summaries are based on analysis counts of 8 and 13. The outcome population is identified as per protocol, but the criteria, exclusions, and missing-data handling are not reported. Those details matter because a per-protocol summary can represent a selected subset of randomized participants.

A further statistical lesson is the distinction between planned and observed information. The registry includes assumptions for a sample-size planning illustration, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such assumptions do not supply a trial-specific sample-size justification, and planning illustrations based on an observed effect are not observed power.

Finally, the trial’s secondary objective is described but has no posted secondary results. A study’s stated aims and the outcomes available for analysis are not interchangeable. Clear reporting of outcome definitions, analysis populations, participant flow, uncertainty estimates, and secondary results is essential for readers to understand what a trial’s data can—and cannot—support.

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 primary outcome result is a per-protocol summary, but the registry does not define the analysis population or explain exclusions. It reports outcome analysis counts of 8 and 13, alongside enrollment of 27, without participant-flow information or an explanation for the difference. The representativeness of the analyzed participants therefore cannot be assessed from the registry record.

No confidence interval, p-value, or formal primary comparison is posted. The record identifies the continuous comparison as not estimable from the available values, so the means cannot be supplemented with a recalculated estimate. The absence of an inferential result limits assessment of precision and statistical compatibility.

The registry does not report how missing outcomes were handled, whether an intention-to-treat analysis was performed, or the criteria for per-protocol inclusion. It also does not give the original sample-size justification, an analysis plan, or details about any interim analyses. These design and analysis details are not recoverable from the posted group means and standard deviations.

The record gives a four-week timeframe for sleep-onset latency but does not post secondary results for CPAP compliance, despite naming it as a secondary objective. It also does not report the specific eligibility criteria or age threshold for the older-adult population, or identify which parties were masked. These gaps constrain assessment of applicability and trial conduct without indicating what the unreported details would have shown.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Treatment of Insomnia in Elderly Sleep Apnea Patients With Ramelteon (TAK 375) — NCT01048242.
• Registry record last updated 2023-05-25; status last verified 2023-05.
• Results first posted 2017-05-03.
• 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

The registry describes a completed, randomized, quadruple-masked, parallel-group Phase 3 trial sponsored by the University of Pennsylvania. It lists enrollment of 27, a start of 2006-07, and primary completion in 2009-03. The comparison was ramelteon 8 mg orally before bedtime versus a sugar pill in older adults with insomnia and obstructive sleep apnea.

The primary outcome was polysomnography-determined sleep-onset latency in minutes at four weeks, summarized as a mean and standard deviation for a per-protocol population. The posted means are 9.7 minutes for ramelteon and 34.4 minutes for the sugar pill; the corresponding standard deviations are 10.3 and 30.7. No formal comparison, p-value, or confidence interval is reported.

CPAP compliance was a stated secondary objective, but no secondary outcome results are posted. The registry does not explain the difference between enrollment and the primary outcome analysis counts or report missing-data handling. Safety summaries list 0 serious adverse events in each group; other adverse events are listed for 4 participants in the ramelteon group and 2 in the sugar-pill group.