The Effect of Donepezil (Aricept(Registered Trademark)) on REM Sleep in Children With Autism: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effect of Donepezil (Aricept(Registered Trademark)) on REM Sleep in Children With Autism (NCT00695136), a na phase 1, phase 2 study. The primary outcome is Change in Percentage of Time That Subjects With Autism Spend in REM Sleep..

2. Clinical Question

The study’s stated aim was to test whether donepezil could increase REM sleep in children with autism or an autism spectrum disorder. The registry background notes that some children in this population spend relatively little time in REM sleep, and that reduced REM sleep has been associated with learning and behavior problems in some studies. Those statements provide the rationale for examining sleep; they are not findings from this study and do not establish that changing sleep would change learning or behavior.

The registry describes screening that included medical history, physical and neurological examinations, blood tests, an electroencephalogram, and a sleep study. Sleep assessment involved overnight monitoring at the NIH Clinical Center. The description says participants might be required to have up to six overnight stays for sleep studies. These details indicate that the research question concerned a measured sleep characteristic under monitored conditions, rather than a comparison of clinical outcomes between treatment groups.

3. Trial Design

This was a completed, open-label, single-group study, with phases listed as Phase 1 and Phase 2. The registered enrollment was 17. The study was sponsored by the National Institute of Mental Health. The registry lists a start date of 2008-06 and a primary completion date of 2011-01.

Because the study had a single group and no masking, the design did not include a concurrent randomized control group or blinded treatment assignment. The registered allocation is NA. As a result, the primary question is framed around change from baseline within the same group, not a difference between treatment and control arms. A before-and-after change can describe what happened over the observed period, but by itself it cannot separate a treatment-associated change from changes due to time, measurement variability, or other influences.

The intervention is listed as donepezil hydrochloride, with a behavioral intervention also named as “Increase REM sleep percentage.” The arm description identifies an open-label single arm receiving donepezil. The available summary says children started at 1.25 mg; the dose schedule after that point is not reported in the registry record. The endpoint timeframe is one month, from baseline to the 1.25 mg dose.

The registry describes eligibility as children between 2 and 10 years of age with autism or an autism spectrum disorder and a low REM sleep percentage relative to the average for their age. The study description includes screening and overnight sleep monitoring. Details such as the final eligibility criteria, the number screened, and the number completing each assessment are not reported in the registry record. The registered enrollment should therefore not be treated as evidence that every enrolled participant contributed data to the primary endpoint.

No randomized comparison is available for interpreting the primary sleep measure. Accordingly, the study can address the observed within-group change as registered, but cannot estimate a treatment-versus-control contrast from the design described in the record.

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: Children were screened with polysomnography and 8 of 16 subjects were found to have low REM sleep% and were eligible to continue with the study. One of the 8 elected not to participate in the dose-finding drug administration.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: 16 subjects completed screening and had baseline data. However, only 8 of them were eligible for further study participation and only 5 completed the drug and provided data for analysis.

6. Primary Endpoint

The registry lists the primary outcome as Change in Percentage of Time That Subjects With Autism Spend in REM Sleep., measured over 1 month (from baseline to 1.25 mg dose).

The primary endpoint is the change in the percentage of time that participants with autism spent in REM sleep. It is specified as a mean, with standard error as the dispersion measure, over one month from baseline to the 1.25 mg dose. In plain terms, it concerns how the group’s average share of sleep classified as REM changed between the named assessments.

REM sleep is the feature of sleep the study set out to measure. The registry rationale connects interest in REM sleep with reports that some children with autism have relatively little REM sleep and with associations, in some studies, between reduced REM sleep and learning or behavior problems. The endpoint therefore addresses a sleep measure that motivated the study. It is not itself a measure of learning, behavior, or broader clinical benefit.

A mean summarizes the group’s average change, while a standard error describes the statistical precision of that estimated mean under the analysis used. The standard error is not the spread of individual children’s changes; it reflects uncertainty in the estimated group mean. General interpretation of the estimate would require the actual mean change and its uncertainty. Neither the numerical mean change nor its standard error is reported in the registry record, so the size and precision of the observed endpoint cannot be assessed from this record.

The record does not describe the exact sleep-scoring procedure or specify whether the endpoint was calculated from all enrolled participants or a subset. Those details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registered outcome is continuous: it is a percentage of sleep time, summarized as a mean. For a continuous measurement, an average describes the central level of the observations on the measurement scale. A mean change describes the average difference between the recorded values at the specified assessments. The registry names the assessments as baseline and the 1.25 mg dose, over one month.

What does the standard error describe?

In general, a standard error describes the uncertainty of an estimated quantity, such as a sample mean, arising from sampling variability under the statistical model. A smaller standard error indicates a more precisely estimated mean, while a larger standard error indicates greater uncertainty. It is not interchangeable with the standard deviation: a standard deviation describes variation among observations, whereas a standard error describes precision of an estimate. The record names standard error as the dispersion measure but does not provide its value for the primary endpoint.

A confidence interval is a range constructed by a statistical procedure to express uncertainty around an estimate. General interpretation considers both the estimate and the interval: a narrow interval implies more precision than a wide interval, while an interval that spans values in different directions may leave the direction or size of an effect uncertain. No confidence interval for the primary endpoint is reported in the registry record. Without the estimate and its uncertainty, readers cannot evaluate the observed change’s precision or how compatible the data are with different possible changes.

Why does the single-group design matter?

In a randomized comparison, treatment groups can provide a basis for estimating a between-group contrast, subject to the design and analysis. This study is listed as a single-group, open-label study, with allocation recorded as NA and masking as none. The registered primary endpoint is instead a baseline-to-follow-up change within the group. Such a comparison uses each participant’s earlier measurement as a reference, but the earlier measurement is not a concurrent untreated control. It cannot by itself distinguish an intervention-associated change from changes that might also occur over time.

General sources of uncertainty in a before-and-after measurement include natural fluctuation, changes in measurement conditions, and regression to the mean. Regression to the mean refers to the tendency for an unusually high or low measurement to be less extreme when repeated, in part because measurements include random variation. It is a general consideration when eligibility is based on an unusually low baseline measurement; it is not evidence that a particular participant’s measurement changed for that reason.

Open-label status means that the record does not describe masking. Knowledge of treatment can influence some aspects of study conduct or assessment in general, though the registry does not report whether or how that affected sleep measurement in this study. The sleep endpoint is a measured physiological characteristic, but its assessment still depends on procedures for recording, scoring, and selecting usable observations. Those procedures are not reported in the registry record.

What can a mean conceal?

A group mean can summarize an average while hiding differences in individual responses. Participants may have changes in different directions or of different magnitudes, and the average alone does not show that pattern. The registry record provides no participant-level distribution or other summary of individual changes. Consequently, it is not possible to infer how consistent any change was across participants.

The endpoint is expressed as a percentage of REM sleep time. Percentage measures can be influenced by the way the denominator and scoring interval are defined. The record does not specify those operational details, the scoring rules, or the treatment of incomplete or unusable sleep recordings. These are methodological details, not values that can be inferred from the endpoint title.

How should planning illustrations be read?

Sample-size calculations are planning tools: they illustrate how many participants might be needed under stated assumptions to detect a target effect with a chosen statistical approach. The stated assumptions for the planning illustration are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and a target effect expressed as a fraction of the observed effect. The illustration is not the registered design, which is single-group, and it should not be interpreted as an observed study result or as observed power.

In general, a planning calculation depends on the effect size, variability, allocation, significance level, and power target assumed. If assumptions differ from the eventual study or population, the illustration may not match what the study could detect. The registry does not report the study’s own sample-size justification, or whether a formal prospective calculation was used. No conclusion about adequacy of enrollment follows from the planning assumptions alone.

The record identifies the endpoint as a mean with standard error, but does not provide an analysis method, model, test, confidence interval procedure, or adjustment strategy. These methods are not reported in the registry record. A particular statistical test or model should not be inferred solely from the outcome’s continuous scale or its summary measure.

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("Open Label Single Arm")
n   <- c(5)
m   <- c(9.2)
sp  <- c(2.6)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
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  Open Label Single Arm  5  9.200  5.814  1.981  16.419

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure, the change in the percentage of time spent in REM sleep, and no analysis entries. That does not establish whether the study examined additional outcomes, time points, or exploratory analyses; those details are not reported in the registry record. A multiplicity strategy for handling multiple statistical tests is also not reported. In general, when several hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis accounts for the testing strategy. No such adjustment or testing plan can be inferred.

The record does not state how missing sleep assessments were handled, whether all enrolled participants were included in the primary analysis, or how participants who did not complete an assessment were treated. The analysis population is not reported in the registry record. The registered enrollment of 17 should not be assumed to equal the number analyzed for the primary outcome.

The endpoint description specifies a baseline assessment and an assessment at the 1.25 mg dose over one month, but the record does not report rules for incomplete recordings, exclusions after enrollment, or deviations from the intended assessment schedule. It also does not report a statistical analysis plan or whether analyses were prespecified. These omissions limit assessment of the risk of selective reporting and of how the primary estimate, if calculated, would relate to all enrolled participants.

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 reports adverse-event counts for the open-label single arm. For serious adverse events, seven participants are listed as at risk and zero as affected. For other adverse events, seven are listed as at risk and one as affected. These are registry counts, not estimates of comparative risk against a control group.

The record does not provide serious adverse-event terms, and the list of top serious terms is empty. It does not define the “other” event category in the information or provide event descriptions for the affected participant. It also does not report event timing, severity grading for other events, attribution to treatment, or whether events led to a change in participation. These details are not reported in the registry record.

Adverse-event counts should be read separately from the primary sleep endpoint. The risk sets reported for safety do not establish the number included in the primary outcome analysis. Because this was a single-group study, the listed counts cannot by themselves indicate whether event frequency differed from what would have occurred without the intervention. The small reported risk sets also mean that the registry counts alone offer limited information about uncommon events. No treatment recommendation follows from these figures.

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

The study addresses a focused physiological question: whether mean REM sleep percentage changed between baseline and the assessment at the 1.25 mg dose over one month in children with autism. The registry makes clear that the study used an open-label, single-group design. Its primary endpoint is a mean change, with standard error specified as the measure of dispersion.

However, the registry record does not report the numerical change or its standard error. It therefore does not establish the direction or magnitude of the observed result, or how precisely it was estimated. The record also does not provide a confidence interval or p-value for the primary endpoint. It is not possible to state from the registered outcome description whether REM sleep increased, decreased, or remained similar.

Even if a before-and-after change were available, the design would not provide a randomized comparison with an untreated or alternative-treatment group. A change over time in a single group can be described, but it cannot isolate the intervention’s effect from other explanations. Selecting children based on low REM sleep relative to an age-based average is another reason to interpret within-group change cautiously, because repeat measurements can vary. These are general limitations of the design and selection approach, not claims about the study’s actual unreported result.

The primary endpoint is a sleep measure, not a direct assessment of learning or behavior. The registry background discusses associations between reduced REM sleep and learning or behavior problems in some studies, and describes future research as a possible next step if REM sleep can be increased. Those background statements do not show that this study measured or changed learning or behavior. Such outcomes are not listed as the primary endpoint in the record.

The safety counts document the registry’s reported serious and other adverse-event figures for the listed risk sets, but they do not provide a controlled safety comparison. The available information is therefore descriptive and does not establish a comparative safety profile.

The appropriate reading is limited: the record documents the study question, design, endpoint definition, and some safety counts, but not a numerical primary result. It cannot support a claim that the intervention did or did not change REM sleep, nor a claim about effects on learning, behavior, or outcomes beyond those reported.

14. Why This Trial Matters Statistically

This trial is statistically instructive because its objective and design need to be kept distinct. The objective concerns whether REM sleep changes after donepezil, while the registered design is a single-group, open-label study. The endpoint is a within-group change from baseline, not a randomized treatment contrast. Recognizing that distinction helps prevent a descriptive before-and-after comparison from being interpreted as a causal estimate.

The eligibility description also matters for interpretation. Candidates were described as having REM sleep percentage well below the age-based average. Selecting participants because of a low measurement can make repeat measurement and regression to the mean important general considerations. A concurrent comparison group can help contextualize changes over time, but this record does not describe one.

The record also illustrates why an endpoint definition is not the same as a reported result. It specifies a continuous outcome, a mean, a standard error, and a timeframe, but no numerical endpoint estimate is reported. Without an estimate and its uncertainty, readers cannot judge effect size or precision. An endpoint label alone does not establish whether the intended change occurred.

Finally, planning calculations should not be confused with observed evidence. The stated assumptions describe a sample-size planning illustration involving equal allocation between two arms, despite the registered study being single-group. Such an illustration is not observed power and is not a substitute for the trial’s result or original design justification. In this case, the registry does not report the study’s own sample-size rationale.

The statistical value of this record is therefore in clarifying what the study was designed to ask and what its registration does not allow readers to conclude. It highlights the roles of a comparator, uncertainty estimates, analysis details, and complete outcome reporting in evaluating clinical research.

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 most consequential limitation for interpreting the primary endpoint is that no numerical outcome estimate is reported in the registry record. The endpoint is defined, but its mean change and standard error are absent. The record also lacks a confidence interval and p-value. The result’s direction, magnitude, and precision therefore cannot be assessed.

The single-group, open-label design has no concurrent randomized control comparison. A baseline-to-follow-up change cannot by itself distinguish an intervention-associated change from time effects, natural variability, measurement variability, or other influences. As the eligibility description selects children with low REM sleep relative to an age-based average, regression to the mean is a relevant general consideration.

The record does not state how many enrolled participants contributed primary outcome data, how missing or unusable sleep recordings were handled, or which analysis population was used. It does not describe the sleep-scoring method, rules for data exclusions, or the statistical model or test. These omissions make it difficult to assess how the endpoint would have been calculated and how robust its interpretation would be.

The treatment description in the available summary is incomplete: it says children started at 1.25 mg, but the full dosing schedule is not reported in the registry record. The record also does not report detailed adherence, changes in treatment, or the relationship between each participant’s exposure and sleep assessment.

Finally, the record lists one outcome measure and no analysis entries, but does not establish whether additional outcomes or analyses were conducted. A multiplicity plan and the study’s own sample-size justification are not reported. Safety information is limited to the listed counts; event terms and further clinical details are not available. These limitations constrain both outcome interpretation and assessment of the completeness of reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Effect of Donepezil (Aricept(Registered Trademark)) on REM Sleep in Children With Autism — NCT00695136.
• Registry record last updated 2013-04-24; status last verified 2013-04.
• Results first posted 2013-04-24.
• 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 Phase 1 and Phase 2 study of donepezil hydrochloride in children with autism or an autism spectrum disorder. It was open-label and single-group, with registered enrollment of 17. The registry lists a start date of 2008-06 and a primary completion date of 2011-01, and identifies the National Institute of Mental Health as sponsor.

The primary endpoint is change in mean percentage of time spent in REM sleep from baseline to the 1.25 mg dose over one month, with standard error named as the dispersion measure. The registry record does not report a numerical result or analysis estimate for this endpoint. It lists serious adverse events as zero affected among seven at risk and other adverse events as one affected among seven at risk.

The record does not provide a randomized control comparison, primary outcome analysis details, or information on missing outcome data. Its registered endpoint definition and safety counts can be described, but the primary result’s direction and precision cannot be evaluated from the registry record.