Safety and Efficacy of Chronic Hypnotic Use 2: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Chronic Hypnotic Use 2 (NCT02456532), a randomized phase 4 study. The primary outcome is Total Number of Capsules Taken During Discontinuation From Either Active Drug vs Placebo Over a Two Week Period.

2. Clinical Question

The registry describes the study as assessing risks for transition from therapeutic hypnotic use to abuse. Its primary outcome, however, concerns capsule choice during discontinuation. That distinction matters when interpreting what the posted results can address: the outcome can describe behavior in the study’s discontinuation period, but it does not by itself establish whether participants transitioned to abuse. The registry record does not report a separate primary outcome that directly counts such transitions.

3. Trial Design

The registry record identifies this as a phase 4, randomized, triple-masked, parallel-group study, with an enrollment of 41. It is marked completed. The recorded start date is 2015-08-05, and the primary completion date is 2022-02-22. Henry Ford Health System is listed as the sponsor.

Three groups are described: placebo, zolpidem CR and eszopiclone. The arm descriptions specify six months of nightly treatment. The zolpidem CR arm is listed at 12.5 mg nightly, and the eszopiclone arm at 3 mg nightly. Placebo was taken nightly for the same six-month period. The registry also lists a secondary outcome concerning percent of time asleep over time in bed during the two-week discontinuation period.

The record gives 14 participants in the placebo group, 11 in the zolpidem CR group and 16 in the eszopiclone group for the posted primary outcome. These are the group sizes associated with the reported means and standard deviations, not a description of every analysis population or participant flow. The method used to generate the random allocation, allocation concealment, exact masking procedures, eligibility criteria and participant flow are not reported in the registry record.

The parallel design means the posted arms represent separate groups rather than repeated treatment periods for each participant. The primary comparisons contrast each active-drug group with placebo. Although an overall ANOVA is also listed among the reported analyses, the registry record does not provide its degrees of freedom, test statistic or a detailed account of how it relates to the pairwise comparisons.

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 Total Number of Capsules Taken During Discontinuation From Either Active Drug vs Placebo Over a Two Week Period, measured over total number of capsules chosen in week 1 and week 2 of the discontinuation period.

The primary endpoint is the total number of capsules chosen across week 1 and week 2 of the two-week discontinuation period. The registry describes an instruction to stop nightly hypnotic use and an option to choose 1, 2 or 3 capsules if necessary. The outcome is recorded as a mean with a standard deviation, and its unit is the total number of capsules chosen.

This measure provides a numerical summary of capsule choice during the specified period after six months of nightly placebo or active-drug use. Comparing group means gives one way to describe differences in average capsule choice between each active-drug arm and placebo. The standard deviation describes how much individual values vary within each group; it is not the uncertainty around the group mean.

The endpoint is relevant to the proposal’s interest in hypnotic use during discontinuation, but its scope is specific. Capsule choice is not itself a diagnosis of abuse, a direct measure of a transition to abuse, or a complete measure of hypnotic use outside this protocol. The registry does not report a definition linking a particular capsule count to abuse or misuse. It also does not explain whether chosen capsules were taken, or how choices were recorded beyond the description of the outcome. Those distinctions limit the claims that can be made from this endpoint alone.

7. Results Posted in the Registry

• Zolpidem CR: mean 2.60 versus 0.43 on control; difference 2.17 (95% CI -0.62 to 4.96), standardized effect d = 0.68; z-test p = 0.127.
• Eszopiclone: mean 6.30 versus 0.43 on control; difference 5.87 (95% CI 0.66 to 11.08), standardized effect d = 0.76; z-test p = 0.027.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference represent?

For a continuous outcome, a group mean describes the average value in that group. Here, the outcome is the total number of capsules chosen during the discontinuation period. A mean difference compares the average in one group with the average in another, with the direction depending on which group is subtracted from which. The recalculated comparisons are expressed as the active-drug group mean minus the placebo group mean. A positive value therefore indicates a higher observed mean in the active-drug group in these posted summaries; it does not, by itself, establish why the groups differ or what the difference means clinically.

The standard deviation describes variation among individual observations in a group. It is not a confidence interval and does not directly measure how accurately the mean has been estimated. The posted standard deviations are 1.6 for placebo, 4.5 for zolpidem CR and 10.5 for eszopiclone. General statistical context: when individual outcomes vary widely, a group mean can be estimated less precisely unless there is enough information to offset that variability. The relatively small group sizes and the observed spread are important context for reading the estimates.

What does the confidence interval add?

A confidence interval gives a range of values compatible with the data and the method used to calculate it, while representing uncertainty in the estimated difference. It is not a guarantee that the true value lies within that particular interval, nor does it describe the spread of individual capsule counts. For the recalculated zolpidem CR comparison, the interval includes zero, so the data do not distinguish that estimated difference from zero at the conventional two-sided 0.05 level using this unadjusted interval. For the recalculated eszopiclone comparison, the interval excludes zero. These interval statements apply to the simple recalculations, not to a sponsor-reported pairwise estimate.

A p-value describes how incompatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The recalculated p-values of 0.127 and 0.027 correspond to separate unadjusted comparisons. The registry’s reported ANOVA p-value is =0.05. Because the record marks a discrepancy, the sponsor’s own analysis takes precedence over the recalculations.

Why is ANOVA different from two pairwise comparisons?

ANOVA is a method for assessing whether the means across multiple groups are compatible with a common mean under its model. An overall ANOVA result does not identify which pair of groups differs. Pairwise comparisons address specified group pairs, such as zolpidem CR versus placebo or eszopiclone versus placebo. When several comparisons are made, the chance of finding at least one nominally small p-value can increase. A multiplicity procedure can account for that issue, but the registry record does not report whether any adjustment was used for the sponsor’s analysis or for the intended primary comparisons.

General statistical context: standard methods for mean comparisons rely on assumptions about how observations behave, including independence and an appropriate model for variation. Capsule counts are discrete outcomes, and the posted standard deviations are large relative to the group means in the active-drug arms. This does not prove that a particular assumption was violated. It does make the distribution of individual values and the robustness of the chosen analysis relevant; those details are not reported in the registry record. The posted summary statistics do not allow a reader to inspect the individual outcome distribution.

What can be inferred from summary-statistic recalculations?

The recalculated pairwise estimates use the posted arm means and standard deviations and are simple, unadjusted comparisons. They are not adjusted for other participant characteristics, do not incorporate an unreported analysis population and do not resolve the difference from the sponsor’s analysis. They also cannot reproduce the sponsor’s exact procedure because the registry gives no further test details. The estimates are useful for understanding the scale and uncertainty of the posted group contrasts, but should not be mistaken for a reanalysis of participant-level records.

The registry record does not report the statistical analysis plan, model details, covariate adjustments, treatment of outliers, missing-data procedures, or the precise population used for the ANOVA. It also does not explain whether the study’s outcome was analyzed according to the originally planned approach. General statistical context: when important analysis choices are not documented, readers have less ability to judge whether results are robust to reasonable alternatives. The reported statistics should therefore be interpreted alongside the limits of the record, rather than as a complete account of the analysis.

10. Confidence Intervals and Precision

The recalculated mean difference for zolpidem CR versus placebo is 2.17 capsules. Its confidence interval includes zero, and the interval is broad enough to be compatible with values on either side of zero. The recalculated mean difference for eszopiclone versus placebo is 5.87 capsules; its confidence interval excludes zero but also spans a wide range of possible differences. Together with the small group sizes and the sizeable standard deviations, these intervals indicate that the estimates are not highly precise.

A confidence interval describes uncertainty in an estimated group contrast, not the range of values experienced by most participants. The standard deviations describe observed variation among participants, while the confidence intervals concern uncertainty in the estimated mean differences. Keeping those roles separate helps avoid reading a wide interval as though it were a description of individual capsule choices.

The recalculated intervals belong to simple, unadjusted comparisons based on the posted summaries. They do not include any multiplicity correction, and they are not the sponsor’s reported intervals. No confidence interval for the sponsor’s ANOVA result is reported in the registry record. The discrepancy means the recalculated intervals should not displace the sponsor’s analysis; the registry does not provide enough information to determine how the sponsor’s overall result translates into pairwise uncertainty.

Precision is also limited by reporting gaps. The record does not provide participant-level values, a detailed account of missing outcomes, or the analysis population for each comparison. Without those details, readers cannot assess whether the summaries reflect all randomized participants or whether missing observations could affect the estimates.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations give participants per arm, not total events. They are based on the observed effect and use a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. Each planning row uses the stated fraction of the observed effect as the effect to detect. The trial’s original design assumptions and its own sample-size justification are not reported in the registry record.

For the zolpidem CR comparison, planning for 100% of the observed effect gives 35 participants per arm for 80% power and 46 participants per arm for 90% power. Planning for 75% of the observed effect gives 61 participants per arm for 80% power and 82 participants per arm for 90% power. Planning for 50% of the observed effect gives 137 participants per arm for 80% power and 183 participants per arm for 90% power.

For the eszopiclone comparison, planning for 100% of the observed effect gives 28 participants per arm for 80% power and 37 participants per arm for 90% power. Planning for 75% of the observed effect gives 49 participants per arm for 80% power and 66 participants per arm for 90% power. Planning for 50% of the observed effect gives 110 participants per arm for 80% power and 147 participants per arm for 90% power.

In plain terms, the 80% column describes the planned number per arm under these assumptions for an 80% chance of detecting the specified effect if that effect were the true one; the 90% column does the same for a 90% chance. Smaller effects require more participants under the same assumptions. These are planning illustrations, not observed power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 2.170; pooled standard deviation σ = 3.202.
2. n = 2 × (1.96 + 0.842)² × 3.202² / 2.170² = 34.2, rounded up to 35 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 2.17                      # observed difference in means
sigma <- 3.20176581714311                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2456532)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 35 (80% power), 46 (90% power)
 75% of observed effect: n per arm = 61 (80% power), 82 (90% power)
 50% of observed effect: n per arm = 137 (80% power), 183 (90% power)
power.t.test: 35.2 
Simulated power at n = 35 per arm: 0.796 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry’s reported analysis is an ANOVA across placebo, zolpidem CR and eszopiclone, with p = 0.05. It does not report the test statistic, degrees of freedom, confidence interval, detailed pairwise results or the analysis population. The posted recalculations instead compare each active-drug group with placebo using the group means and standard deviations. They are unadjusted pairwise results: a mean difference of 2.17 capsules and p = 0.127 for zolpidem CR, and a mean difference of 5.87 capsules and p = 0.027 for eszopiclone.

The registry record flags a discrepancy between the sponsor’s analysis and the recalculation. The sponsor’s own analysis takes precedence. The pairwise calculations can help describe the posted summaries, but they do not replace the sponsor’s overall analysis or establish how that analysis would compare the individual arms. An overall ANOVA and pairwise comparisons answer different questions, and the record does not give enough detail to reconcile the reported p-value with the recalculated contrasts.

No further explanation of the discrepancy is reported in the registry record. In particular, it is not clear whether the methods, analysis population or handling of variation differed. Readers should not treat the unadjusted recalculated p-values as the sponsor’s findings.

14. Multiplicity, Missing Data and Analysis Populations

The posted results include two active-drug-versus-placebo recalculations and a sponsor-reported ANOVA across three groups. Multiple comparisons raise a general statistical issue: when several hypotheses are tested, the probability of at least one apparently unusual result can increase if each test is judged separately without adjustment. An adjustment can control that risk, but may change the interpretation of individual p-values and confidence intervals.

The registry record does not report whether the sponsor adjusted for multiple comparisons, which comparisons were designated primary, whether the ANOVA was intended as a gatekeeper for pairwise tests, or whether any other testing hierarchy was specified. The pairwise recalculations are unadjusted. Their p-values should therefore be understood as nominal results rather than as multiplicity-adjusted evidence. The registry’s reported p = 0.05 does not resolve this issue because the record does not provide further detail about the analysis.

The record lists an enrollment of 41 and outcome group sizes, but does not describe the analysis populations or provide participant flow. It does not report whether all randomized participants were included, whether participants were analyzed according to assigned group, or how protocol deviations were handled. Those details matter because an analysis of everyone assigned to a group may differ from an analysis restricted to participants with complete outcome data or adherence to protocol.

Missing-data handling is also not reported in the registry record. There is no description of how missing capsule counts were handled, whether any values were imputed, or how many outcomes were unavailable. Without that information, it is not possible to determine whether the displayed group summaries represent complete outcome data or how missingness might affect the estimates.

The statistical analysis plan, model specifications, and any prespecified interim analyses are not reported in the registry record. The record also does not explain whether the endpoint and analysis were finalized before results were examined. These gaps do not establish that the analysis was inappropriate; they limit independent assessment of the analysis choices and their relationship to the reported results.

15. 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.

The registry lists serious adverse events for 0 of 14 participants at risk in the placebo group, 0 of 11 at risk in the zolpidem CR group and 0 of 16 at risk in the eszopiclone group. It also lists other adverse events for 0 of 14, 0 of 11 and 0 of 16 participants at risk in those respective groups. Deaths are listed as 0 in each group. No serious adverse event terms are listed.

These figures mean that the registry reports no participants affected in the listed serious or other adverse-event categories for the groups and counts shown. They do not establish that no events of any kind occurred outside the reported categories, nor do they show that the groups have identical safety profiles. With the group sizes shown, the record gives limited information about uncommon events. The registry does not provide additional detail about event collection, definitions or the period covered by these adverse-event counts, so the figures should be read as the posted safety reporting rather than as a comprehensive account of all possible harms.

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

The posted outcome measures the total number of capsules chosen during a two-week discontinuation period after six months of nightly placebo or active-drug use. The observed mean was 0.43 in the placebo group, 2.6 in the zolpidem CR group and 6.3 in the eszopiclone group. The unadjusted recalculations estimate higher average capsule counts for each active-drug group than for placebo, but the sponsor-reported analysis differs and takes precedence.

The endpoint does not directly measure abuse or a transition from therapeutic use to abuse. A higher mean capsule count in this specific setting cannot, on its own, be interpreted as a diagnosis, a measure of dependence, or evidence about behavior beyond the study period. The registry does not report a rule that maps capsule choice to abuse or misuse. The results therefore address a narrower behavioral measure than the broad risk question described in the study proposal.

The posted statistics also do not establish that any observed group difference was caused by the assigned drug. Randomization is recorded, but details of allocation, analysis population, missing outcomes and protocol adherence are not available in the registry record. The recalculated intervals are uncertain, and the sponsor’s analysis is not described in sufficient detail to resolve the discrepancy. These considerations restrict how confidently the numerical differences can be interpreted.

Nor do the results establish equivalence between groups. A result that is not statistically distinguishable from zero in an unadjusted comparison does not demonstrate that the groups are the same. Conversely, a nominally small p-value in a recalculation does not by itself establish clinical importance or a broader effect. The findings should be read as estimates of capsule choice in this trial, with limited precision and incomplete analysis reporting.

17. Why This Trial Matters Statistically

This trial illustrates why an outcome’s definition matters as much as the broad research question. The proposal concerns risks for transition from therapeutic hypnotic use to abuse, while the primary posted measure is capsule choice during a two-week discontinuation period. That measure may describe behavior in the study setting, but it is not interchangeable with a direct measure of abuse. Statistical interpretation should follow the endpoint actually recorded, rather than extending the result to a broader concept the endpoint does not directly assess.

The record also shows the difference between an overall group test and pairwise comparisons. An ANOVA result across three arms does not identify which particular arm differs from placebo. The unadjusted recalculations add pairwise estimates and confidence intervals, but a recorded discrepancy means the sponsor’s own analysis takes precedence. Without details of the analysis plan or multiplicity handling, a reader cannot treat those recalculations as a definitive substitute.

Finally, the trial emphasizes how sample size, variability and reporting shape interpretation. The outcome means are accompanied by substantial standard deviations, and the recalculated intervals are broad. Planning illustrations show how required participants per arm increase when a smaller effect is targeted, while remaining distinct from the trial’s original design assumptions. These are useful statistical lessons about precision and analysis transparency, not grounds for a medical recommendation.

18. 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 is a measure of capsule choice during discontinuation, not a direct measure of transition to abuse. The registry does not report a definition that connects the outcome to abuse or misuse, nor does it explain whether chosen capsules were taken. The result therefore has a narrower interpretation than the study’s broad stated objective.

The group sizes associated with the primary summaries are 14 for placebo, 11 for zolpidem CR and 16 for eszopiclone. The standard deviations are sizeable relative to the means, and the recalculated confidence intervals indicate uncertainty in the group contrasts. The registry does not provide individual-level data or outcome distributions, which limits assessment of the behavior of this count outcome and the sensitivity of the results to unusual values.

A discrepancy is recorded between the sponsor’s analysis and the unadjusted recalculations. The sponsor’s own analysis takes precedence, but details needed to understand the difference are not reported in the registry record. The ANOVA result is listed without a test statistic, degrees of freedom or confidence interval, and the record does not report multiplicity procedures or an analysis plan.

Further details are not reported in the registry record, including participant flow, missing-data handling, analysis populations, randomization procedures, eligibility criteria, masking procedures, protocol deviations and the original sample-size justification. The adverse-event data are limited to the counts and categories posted. These omissions restrict evaluation of precision, potential bias, generalizability and safety reporting. They do not, by themselves, establish that any particular limitation altered the observed results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Efficacy of Chronic Hypnotic Use 2 — NCT02456532.
• Registry record last updated 2024-03-29; status last verified 2023-07.
• Results first posted 2024-03-29.
• 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.

22. Record Summary

The registry record describes a completed, randomized, triple-masked, parallel phase 4 study of placebo, zolpidem CR and eszopiclone in chronic insomnia, with enrollment of 41. The primary outcome was the total number of capsules chosen during a two-week discontinuation period after six months of nightly study treatment.

Posted group means were 0.43 capsules for placebo, 2.6 for zolpidem CR and 6.3 for eszopiclone. The registry reports an ANOVA with p = 0.05. Unadjusted recalculations give mean differences of 2.17 capsules for zolpidem CR versus placebo and 5.87 for eszopiclone versus placebo; the record flags a discrepancy, so the sponsor’s own analysis takes precedence.

The outcome describes capsule choice, not a direct transition to abuse. The record does not report key analysis details, including missing-data handling, analysis populations and multiplicity procedures. Serious adverse events, other adverse events and deaths are listed as zero in each group.