Ramelteon as an Adjunct Therapy in Non-Diabetic Patients With Schizophrenia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ramelteon as an Adjunct Therapy in Non-Diabetic Patients With Schizophrenia (NCT00595504), a randomized phase 4 study. The primary outcome is Change in Waist Circumference.

2. Clinical Question

The registry describes the study as a test of adding ramelteon to ongoing antipsychotic treatment. The primary outcome focused on waist circumference, while the study summary also lists questions about how the body processes fat and sugar, insulin response, triglycerides, sleep quality, and movement disturbances. The registry record does not report results for those additional questions in the posted outcome results.

The clinical question is narrower than whether ramelteon changes overall health or metabolic risk. It concerns a measured body dimension over the stated follow-up period and a comparison between randomized groups. Waist circumference can serve as a measure of abdominal size, but the record does not report a direct measure of diabetes, heart disease, or long-term clinical outcomes as the primary endpoint. Nor does it provide enough information to draw conclusions about the effects of ramelteon beyond the reported outcome.

The reported primary outcome is labeled as change in waist circumference, with measurements scheduled at baseline and Week 8. However, the registry record does not make clear whether the arm-level values posted in the results represent changes from baseline or measurements at a particular visit. That distinction matters when interpreting the reported means.

3. Trial Design

This was a Phase IV, randomized, parallel-group study sponsored by Massachusetts General Hospital. The registry describes quadruple masking. The trial was marked completed, with an enrollment of 25. Its registered start was 2008-01, and its primary completion was 2010-03.

Participants were assigned to ramelteon or placebo, with both treatments studied as additions to antipsychotic medication. The ramelteon arm is described as receiving 8mg/day; the comparator is described as a sugar pill. A parallel design compares groups treated during the same trial period rather than comparing each participant only with their own earlier treatment. Randomization is intended to make treatment groups comparable on average, although it does not guarantee balance on every characteristic, especially in a small study.

The primary outcome was change in waist circumference, measured at baseline and Week 8. The registry describes the analysis population as participants who completed the study, calling this an intent-to-treat population. The primary outcome results list 14 participants in the ramelteon group and 6 in the placebo group. These are the counts associated with the posted primary outcome summaries, not the enrollment count. The record does not explain why the outcome analysis counts differ from the enrollment figure or from the safety counts.

The posted arm-level primary outcome summaries are means with standard deviations. The ramelteon group is reported with a mean of 106.1 cm and a standard deviation of 8.8; the placebo group is reported with a mean of 108.4 cm and a standard deviation of 6.5. The endpoint is labeled as a change measure, but the posted summary does not clarify whether those values are change scores or waist measurements at a particular visit.

The registry record does not report a formal between-group estimate, confidence interval, p-value, or detailed statistical analysis plan. It also does not report a sample-size justification for the trial. The study’s stated design features identify how the comparison was organized, but they do not establish how precise the estimated treatment contrast is.

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: After providing written informed consent, subjects underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV (SCID). All subjects were screened and enrolled based on eligibility criteria. Baseline study assessments were completed prior to intervention.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The number of participants for analysis (intent to treat) were those that completed the 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 Change in Waist Circumference, measured over Baseline and Week 8.

The primary endpoint is titled “Change in Waist Circumference” and is measured in centimeters. The registry describes a comparison between the ramelteon and placebo groups using waist circumference measured at baseline and Week 8. The posted summaries give an arm-level mean and standard deviation for each group.

Waist circumference is a continuous measurement: it can take many values along a scale, rather than being limited to categories such as present or absent. A continuous endpoint can retain information about the degree of a measurement, which can be useful when evaluating whether groups differ in their average values. Waist circumference is also a direct measure of body size around the waist, relevant to the study’s stated interest in abdominal size and metabolic effects.

The record’s presentation leaves an important interpretive detail unresolved. Although the endpoint title and description refer to change from baseline, the registry does not specify in the posted summary whether 106.1 cm and 108.4 cm are means of individual changes or measurements at a specific visit. A mean change would describe average movement from baseline; a visit-specific mean would describe average waist circumference at that time. These are not interchangeable quantities. The record also does not report a baseline mean for either group or an adjusted comparison.

Thus, the endpoint identifies what the study intended to compare and when waist circumference was assessed, but the available result summaries alone do not provide a fully specified estimate of the between-group change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is continuous and summarized using a mean and standard deviation. These statistics describe the center and spread of the observed values within each arm. They are descriptive: by themselves, they do not quantify uncertainty about the treatment comparison. The registry record does not report an inferential analysis for the primary outcome.

What does a mean describe?

A mean is the arithmetic average of the values in a group. For a continuous measure such as waist circumference, it provides a compact description of the group’s central value. It does not show whether most observations cluster near that value or whether the average is influenced by unusually high or low observations. A mean also does not describe the change experienced by every participant; individual responses can vary around it.

What does a standard deviation describe?

A standard deviation describes how dispersed observed values are around their group mean. A larger standard deviation indicates more spread in the measurements, while a smaller one indicates that values are more closely grouped around the mean. It is not the uncertainty of the mean and it is not a confidence interval. Standard deviations of 8.8 and 6.5 are reported for the two arms, but the registry does not provide the underlying observations or a distribution plot in the record described by these results.

What would a treatment contrast add?

A treatment contrast would directly estimate how the outcome differs between the randomized groups, according to a specified analysis. For an endpoint defined as change from baseline, that might be a contrast between average changes, or a model-based comparison that accounts for baseline measurements. These approaches can answer related but not identical questions. The registry record does not report which approach, if any, was used. It also does not report an adjusted estimate or a confidence interval for a contrast.

A confidence interval is a statistical range that communicates uncertainty around an estimated quantity under the assumptions of the analysis. It would help readers assess which values of the treatment contrast are reasonably compatible with the observed data and method. A narrow interval would indicate greater precision than a wide interval. No confidence interval for the primary comparison is reported in the registry record, so the precision of the contrast cannot be evaluated from the posted summaries.

A p-value, when reported, describes how compatible the observed data are with a specified null hypothesis under the assumptions of a statistical test. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. No p-value or named test is reported for this endpoint. It is therefore not possible to characterize the primary comparison as statistically significant or not significant based on the registry results.

Why does the endpoint definition matter?

The endpoint title refers to change in waist circumference from baseline to Week 8, while the results are expressed as means in centimeters. If those means are average changes, they represent movement over time; if they are measurements at a visit, they represent the groups’ observed waist circumference at that visit. Baseline values would help readers understand the groups’ starting measurements, and a clear definition of the analyzed value would establish what the mean describes. Neither clarification is included in the posted summary. This is why the arm-level means should not be treated as an explicit between-group estimate of change.

What can randomization and masking establish?

Random allocation is a design method intended to reduce systematic differences in baseline characteristics between treatment groups. In a small study, chance imbalances may still occur. The registry identifies the study as randomized and quadruple-masked, but it does not provide details of the randomization procedure, who was masked, or whether masking was maintained. These design labels do not replace a clear report of the analysis or its uncertainty.

The registry’s planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. The record does not report the resulting participant-per-arm planning figures or the trial’s own design justification. Such planning illustrations are not observed power and do not establish the precision of the completed study. The registry record also does not report an interim-analysis plan or a prespecified statistical analysis plan.

Finally, the registry lists zero posted analyses. This means that the posted result record does not include the inferential analysis needed to connect the descriptive arm summaries to a quantified treatment contrast. The design and summaries can be described, but the strength and precision of statistical evidence for a group difference cannot be determined from these results.

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", "Placebo (Sugar Pill)")
n   <- c(14, 6)
m   <- c(106.09, 108.37)
sp  <- c(8.8, 6.5)
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  14  106.090  8.800  101.009  111.171
CARM  Placebo (Sugar Pill)  6  108.370  6.500  101.549  115.191

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures, but reports zero posted secondary outcomes and zero posted analyses. The primary outcome is change in waist circumference. The study summary mentions other topics of interest, including fat and sugar metabolism, waist size, stomach fat, triglycerides, insulin response, sleep quality, and movement disturbances. The record does not provide posted results for those topics in the outcome information.

When a study evaluates multiple outcomes or multiple comparisons, the chance of at least one apparently unusual result can increase if each is tested separately. Statistical methods for multiplicity can address that issue, but the registry record does not report a multiplicity strategy, a hierarchy of outcomes, or which comparisons were prespecified. No adjustment should be assumed.

The primary outcome population is described in the registry as participants who completed the study, with the label “intent to treat.” That wording is important: an analysis limited to completers is not necessarily the same as an analysis retaining every randomized participant in the group assigned at randomization. The record does not report the number randomized to each arm, the number with missing primary outcome data, or whether any imputation or other missing-data method was used.

The outcome analysis counts are 14 for ramelteon and 6 for placebo. The safety counts at risk are 16 and 9, respectively. The registry record does not explain why these sets of counts differ or how participants with incomplete outcome information were handled. Without those details, the potential influence of missing data on the outcome summaries cannot be assessed. The record also does not report sensitivity analyses for missing outcomes.

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 1% reporting threshold.

The safety information reports zero serious adverse events among 16 participants at risk in the ramelteon group and zero among 9 at risk in the placebo group. It also reports zero other adverse events in the respective groups. No serious adverse event terms are listed. Death counts are not reported in the registry record.

These entries describe events recorded in the safety results; they do not establish that no adverse events occurred outside the reported categories or reporting period. A zero count is an observed result in the listed group, not proof that an event cannot occur. With finite group sizes, uncommon events may not appear in a study even when they are possible. The registry record does not provide additional detail about event definitions, collection procedures, severity categories beyond the serious-event designation, or the observation period for safety reporting.

The safety groups have different at-risk counts from the primary outcome analysis groups. The record does not explain this difference. Safety counts should therefore be read on their own terms and not substituted for the outcome analysis counts. These figures support a description of the events posted in the registry, but do not by themselves establish a comparative safety profile or rule out risk.

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

The result establishes that the registry posted arm-level mean and standard deviation summaries for a primary endpoint labeled as change in waist circumference from baseline to Week 8. It reports a mean of 106.1 cm with a standard deviation of 8.8 for the ramelteon arm, and a mean of 108.4 cm with a standard deviation of 6.5 for the placebo arm. The registry also identifies the associated outcome analysis counts. These are descriptive summaries, not a reported treatment-effect estimate.

The result does not establish the size or precision of the difference between groups. The record includes no confidence interval, p-value, or formal comparison result for the primary endpoint. It does not clearly identify whether the arm-level means are changes from baseline or measurements at a particular visit. Nor does it provide baseline group summaries or explain how the outcome analysis treated missing values. Those gaps limit interpretation of the numerical values and any comparison based on them.

The posted information also does not establish whether any observed difference is clinically important. That judgment would require an interpretable estimate and an appropriate basis for understanding its importance; neither a between-group estimate nor a threshold for meaningful change is reported. Descriptive means should not be used to infer that ramelteon improves or worsens waist circumference.

The safety record reports zero serious and zero other adverse events in the listed at-risk groups, with no serious-event terms listed. Those observations are limited to the registry’s reported counts and do not prove absence of risk. Death counts are not reported in the registry record.

In short, the posted results describe selected arm-level measurements and event counts. They do not establish a causal treatment effect, demonstrate equivalence between treatments, or support a conclusion about broader metabolic, sleep, or clinical outcomes. The registry record does not report results for the additional questions noted in the study summary.

14. Why This Trial Matters Statistically

This study illustrates the difference between descriptive results and an inferential treatment comparison. Arm-level means and standard deviations give readers a sense of the values recorded in each group, but they do not quantify the between-group effect or its uncertainty. Without a clearly defined contrast and confidence interval, readers cannot determine how precisely the primary question was answered.

It also highlights why endpoint wording and result definitions need to align. The primary outcome is labeled as change from baseline, but the posted means are not explicitly identified as change scores or as measurements from a particular visit. A clear account of what was analyzed is essential to interpret whether the numbers describe change over time or the observed level of waist circumference.

The registry describes the analysis population as study completers while calling it intent to treat. That phrasing makes analysis-population details especially relevant: readers need to know who was randomized, who contributed outcome data, and how missing information was handled. The outcome and safety counts differ, and the record does not explain why. These features make it difficult to assess how completely the posted summaries reflect the randomized groups.

Finally, the registry states planning assumptions for an illustrative sample-size calculation but does not report its resulting planning figures or the trial’s own design rationale. Planning calculations and completed-study results answer different questions. A sample-size illustration is not observed power, and it cannot replace reporting the actual estimated effect and its precision. This record therefore provides useful design and descriptive information while showing why transparent analysis reporting is needed for a statistical interpretation.

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 main limitation for interpreting this specific trial is that the registry does not post a formal between-group analysis for the primary outcome. There is no reported treatment contrast, confidence interval, p-value, or named analysis method. As a result, the arm-level means cannot show the precision of the comparison or establish whether the groups differed beyond sampling variability.

The outcome is described as change in waist circumference between baseline and Week 8, but the posted arm-level values are not clearly identified as changes or visit-specific measurements. Baseline means and a clear definition of the analyzed quantity are not reported. This prevents a confident reading of what the means represent and whether they directly answer the stated change question.

The registry identifies the outcome analysis population as completers while using the term intent to treat. It does not report the randomized counts by arm, missing primary outcome counts, reasons for missingness, or methods for handling missing data. The primary outcome counts and safety at-risk counts differ, without an explanation in the registry record. These details limit assessment of participant flow and the possible influence of incomplete follow-up.

The record lists three outcome measures but posts no secondary outcome results and no analyses. It does not report whether outcomes or comparisons were prioritized in advance, or whether multiplicity was addressed. It also gives planning assumptions without the calculated planning figures or a trial-specific sample-size justification. These omissions restrict assessment of the analysis plan and the scope of conclusions that can be drawn from the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ramelteon as an Adjunct Therapy in Non-Diabetic Patients With Schizophrenia — NCT00595504.
• Registry record last updated 2012-09-13; status last verified 2012-08.
• Results first posted 2012-09-13.
• 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

This completed Phase IV study was randomized, quadruple-masked, and parallel-group, with an enrollment of 25. Massachusetts General Hospital was the sponsor. It compared ramelteon 8mg/day with placebo as an adjunct to antipsychotic medication in non-diabetic patients with schizophrenia-related conditions.

The primary endpoint was change in waist circumference measured at baseline and Week 8. The registry posts arm-level means and standard deviations, but does not clarify whether the means are change scores or measurements at a specific visit. It reports no inferential comparison, confidence interval, or p-value for the primary outcome. The analysis population is described as study completers, and the registry does not explain missing-data handling or the differing outcome and safety counts.

Safety results list zero serious and zero other adverse events in each reported group; death counts are not reported in the registry record. The posted information is descriptive and does not establish the magnitude or precision of a treatment effect.