A Trial of the Drug Donepezil for Sleep Enhancement and Behavioral Change in Children With Autism: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial of the Drug Donepezil for Sleep Enhancement and Behavioral Change in Children With Autism (NCT01887132), a randomized phase 2 study. The primary outcome is Nonverbal Developmental Quotient (NVDQ).

2. Clinical Question

The trial asked whether donepezil could affect developmental and behavioral outcomes in young children with autism spectrum disorders, with particular interest in communication, social interaction, and rapid eye movement (REM) sleep. The registry record identifies the Nonverbal Developmental Quotient (NVDQ) as the primary outcome, assessed at baseline and 12 months. It also names REM percentage at several time points as a secondary outcome.

3. Trial Design

This was a phase 2, randomized, double-masked, parallel trial. The registry lists donepezil and placebo as interventions and names three arms: Open-Label Donepezil, Donepezil - Blinded, and Placebo. The arm descriptions are empty, so details about the intended distinctions between the donepezil arms are not reported in the registry record. The record also does not specify who was masked or how allocation was carried out.

The registry lists enrollment as 5 and status as terminated. The study start is recorded as 2013-06, and primary completion as 2015-12. Those dates and status do not establish why the trial ended or whether all planned assessments were completed; that information is not reported in the registry record. The study summary describes children 22 to 44 months of age with autism spectrum disorders and says treatment was to be taken once a day, with monitoring at visits every 3 months.

Randomization is intended to make treatment groups comparable on average, while masking can reduce the influence of treatment knowledge on care, assessment, and reporting. In a parallel design, participants are assigned to a group and followed within that group rather than crossing between treatments. These are general explanations of the design terms; the registry record does not describe the specific procedures used to implement them.

The primary outcome is NVDQ at baseline and 12 months. REM percentage at baseline, 6, 12 and 18 Months is listed as a secondary outcome. The record names 6 outcome measures overall, but details for the other measures are not reported in the registry record. No primary outcome analysis is recorded, and the record does not give a treatment effect, uncertainty estimate, or test result.

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: 5 participants signed consent. Only 4 started the study.

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 Nonverbal Developmental Quotient (NVDQ), measured over Baseline and 12 months.

The primary endpoint is the Nonverbal Developmental Quotient (NVDQ), measured at baseline and 12 months. It is calculated from the Mullen Scales of Early Learning: the nonverbal mental age is the average of the age-equivalent values for Visual Reception and Fine Motor, divided by chronological age in months. The registry describes NVDQ as normalized to a mean score of 100, which indicates average normal IQ. A score less than 100 is described as lower than average; 2 standard deviations below average is considered impaired IQ, approximately lower than 70.

A developmental quotient expresses performance relative to chronological age, making it a way to describe developmental level rather than a raw test score alone. Repeating the measure at follow-up can describe change over time. In a randomized trial, a comparison between groups can help distinguish a treatment-group difference from change that might occur over time in either group. This is a general rationale for such an endpoint, not evidence that a treatment effect was observed in this trial.

The registry record names the measure and assessment times but does not report scores at either time point, changes from baseline, or a comparison between groups. It also does not report a clinically meaningful change threshold. Consequently, the endpoint's direction, size, and precision cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the study as randomized, double-masked, and parallel. These terms describe broad design features, not the details of the statistical analysis. Random assignment is generally used to reduce systematic differences between groups at the start of a trial. Masking is generally intended to limit the influence of treatment knowledge on participants, study staff, or outcome assessment. The record does not state which people were masked or describe the allocation process, so the practical safeguards cannot be assessed from the registry entry.

What would a treatment comparison estimate?

For a continuous outcome such as NVDQ, an analysis could compare follow-up scores between randomized groups, compare changes from baseline, or use another prespecified approach. Each approach has assumptions and can use baseline information differently. The registry record does not report which approach was planned or used. It names baseline and 12 months as assessment times, but gives no group-specific values or primary treatment contrast.

A confidence interval is a general way to express the uncertainty around an estimated effect. A narrow interval indicates greater precision than a wide interval, although interpretation also depends on what values are clinically meaningful. A p-value, when used, measures how compatible the observed data are with a specified null model; it is not the probability that a treatment works or that the null hypothesis is true. No confidence interval or p-value for the primary outcome is reported in the registry record.

Why does the missing comparison matter?

A trial's randomized design can support a comparison only if outcome data and an analysis are available. The registry names multiple arms but does not report a primary analysis comparing them. It would therefore be inappropriate to infer a treatment effect from the design label, the list of arms, or the enrollment field. No recalculation from summary statistics is possible because the relevant outcome summaries are not reported.

The record's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a stated fraction of the observed effect. These are assumptions for a planning illustration, not a report of the trial's statistical plan. Because no observed primary effect is reported, the record does not offer a usable primary effect on which to base such an illustration. Planning sample sizes, when available, are illustrations under assumptions; they are not observed power and do not show what the trial demonstrated.

How should the endpoint be understood?

NVDQ is derived from age-equivalent scores and chronological age, as described in the endpoint definition. A score is a measure, while a treatment effect is a comparison of outcomes across groups under a stated analysis. The normalization reference of 100 and the description of values less than 100 help explain the scale, but they do not establish what happened in this trial. No observed NVDQ distribution, group mean, or change score is reported.

REM percentage is a repeated measure listed at baseline, 6, 12 and 18 Months. Repeated measurements can describe patterns over time, but analyses need to account for the fact that observations from the same participant are related. General methods may model time, group, and their interaction, but the registry does not identify a method for these data or report any REM results. A relationship between REM and behavior would require an analysis of both measures and an appropriate interpretation; no such analysis is reported.

What can be concluded from the count outcome information?

Adverse event data are counts, and their interpretation depends on the group and observation period to which they apply. The registry reports 0 serious events in the listed Open-Label Donepezil group, alongside 4 at risk. It does not provide a full comparison across arms or explain the event-collection period in the posted safety figures. In general, rare events and small groups can produce imprecise estimates; a zero count does not establish that an event is impossible or that risk is absent.

Over-dispersion is a general concern for count data when variability exceeds what a simple count model assumes. Depending on the outcome and data structure, methods can account for that extra variability. Nothing in the registry record indicates that an over-dispersed count model was relevant to the primary endpoint or used in an analysis. The endpoint is a developmental quotient, and no statistical model for it is reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures, identifies NVDQ as primary, and names REM percentage at baseline, 6, 12 and 18 Months as a secondary outcome. It reports 0 analyses. The other outcome measures, their analysis methods, and any hierarchy among secondary outcomes are not reported in the registry record.

When a study examines multiple outcomes, time points, or comparisons, the chance of obtaining an apparently notable result by chance can increase. A statistical plan may address this through a prespecified primary comparison, a testing hierarchy, or an adjustment for multiple testing. These are general methods; the registry record does not report whether any approach to multiplicity was planned or applied. Without reported analyses, there is no basis for assessing how multiple outcomes were handled or for interpreting the results of any outcome as confirmatory.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not state how many participants contributed endpoint measurements, whether follow-up data were incomplete, how missing observations were handled, or whether the analysis followed an intention-to-treat or another population definition. These details matter because missingness can affect both the estimated treatment contrast and its uncertainty. The enrollment field alone does not answer those questions.

The study is listed as terminated, but the registry does not give the reason for termination or explain whether it affected outcome collection or analysis. It is therefore not possible to determine whether missing results reflect uncollected measurements, unreported analyses, or another circumstance.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry record lists one safety group, Open-Label Donepezil. It reports 4 at risk, 0 serious adverse events, 0 other adverse events, and 0 deaths for that group. These are counts in the posted record, not a comparative estimate of risk.

The record does not provide corresponding safety counts for the Donepezil - Blinded or Placebo arms. It also does not report a safety comparison, an observation period for the listed counts, or details about how adverse events were collected. As a result, the figures cannot establish whether event occurrence differed between treatments or whether the recorded group represents all participants exposed to the intervention.

A zero count means that no events of that category are recorded for the group in this entry; it does not prove that such events cannot occur. Small groups can provide limited information about uncommon events, and the registry enrollment of 5 does not indicate how the safety group relates to enrollment across all arms. These limitations restrict interpretation of the safety record.

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

The registry record identifies a randomized trial of donepezil and placebo, an NVDQ primary endpoint, and a secondary REM percentage outcome. It also records that the study was terminated and lists enrollment as 5. These details describe the study and its intended outcomes, but they do not provide evidence of an observed treatment effect.

No primary outcome analysis, NVDQ group results, or treatment-effect estimate is reported. There is consequently no basis in the posted results for saying whether NVDQ differed between treatment groups, in which direction it differed, or how precise an estimate would be. The absence of a reported result should not be interpreted as a finding of no effect or as evidence of equivalence.

Likewise, the registry record does not report REM percentage results or an analysis linking REM to behavioral or developmental changes. The trial summary describes those questions as motivations for the study, but the stated objectives are not themselves findings. No conclusion about a relationship between sleep measures and behavioral outcomes can be drawn from the record.

The listed safety counts are limited to the Open-Label Donepezil group. They do not establish comparative safety across the listed arms. The small enrollment and lack of reported analyses further limit what can be inferred about outcomes or uncertainty.

In statistical terms, the record documents a study question and design but does not report the estimates needed to answer the primary question. The distinction is important: a planned comparison, a named endpoint, and a completed analysis are different kinds of information. Only the first two are described in sufficient detail; a comparative primary result is not reported in the registry record.

13. Why This Trial Matters Statistically

This trial illustrates why a randomized design and a clearly named endpoint are not enough to interpret treatment effects. Randomization can support a fair comparison, but the comparison must also be reported with outcome data and an analysis. The registry record names NVDQ as the primary endpoint but reports no primary analysis or comparative estimate.

The record also highlights the difference between enrollment and analytic information. Enrollment is listed as 5, but the number contributing data to each outcome, the group allocation, and the analysis populations are not reported. A reader cannot infer those details from enrollment alone, or determine the precision of an outcome estimate without its data and uncertainty measure.

Multiplicity is another relevant statistical issue because the registry lists 6 outcome measures and names a repeated secondary measure. Without reported analyses or an account of how outcomes were prioritized, it is not possible to assess whether any reported findings would be exploratory or confirmatory. In this record, no outcome analysis is listed.

Finally, the safety figures show why event counts need context. A zero count in one listed group does not supply a comparison, quantify uncertainty, or establish the absence of risk. The record's limited safety information and terminated status make cautious interpretation especially important. The central statistical lesson is that design features describe how a study is organized, while results require reported data and estimates.

14. 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 principal limitation for interpreting this trial is that the registry record does not report a primary outcome analysis. NVDQ is identified as the primary endpoint, but there are no group results, effect estimate, uncertainty interval, or test result. The record lists 0 analyses, so the treatment contrast cannot be evaluated from the posted results.

Enrollment is listed as 5, and the study status is terminated. These registry entries limit the context available for interpretation, but the record does not explain the termination or indicate how it affected enrollment, follow-up, or analysis. Group sizes and outcome-specific participant counts are not reported, so no further detail about the amount of usable data can be established.

The registry names three arms, but their descriptions are empty. It does not specify the planned allocation process, who was masked, the analysis approach, or the population included in any analysis. It also does not report missing-data handling, multiplicity procedures, or a statistical analysis plan. These omissions prevent assessment of important design and analysis choices.

Only one safety group is listed, with no comparative safety results for the other arms. The record also names 6 outcomes but gives details for only the primary endpoint and one secondary outcome. The other measures and their results are not reported in the registry record. These limits mean that neither efficacy comparisons nor broader safety conclusions can be reconstructed from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Trial of the Drug Donepezil for Sleep Enhancement and Behavioral Change in Children With Autism — NCT01887132.
• Registry record last updated 2017-09-25; status last verified 2017-09.
• Results first posted 2017-09-25.
• 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.

18. Record Summary

The registry record describes a phase 2 randomized, double-masked, parallel trial of donepezil and placebo in children 22 to 44 months of age with autism spectrum disorders. It lists enrollment as 5, status as terminated, a start of 2013-06, and primary completion of 2015-12.

NVDQ at baseline and 12 months is the primary outcome. REM percentage at baseline, 6, 12 and 18 Months is listed as a secondary outcome; 6 outcome measures are recorded overall. No primary outcome analysis or comparative result is reported. The safety record lists one Open-Label Donepezil group, with 4 at risk and 0 serious adverse events, 0 other adverse events, and 0 deaths.

The reason for termination, analysis populations, missing-data methods, and statistical plan are not reported in the registry record.