Trial of Dextromethorphan in Rett Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Dextromethorphan in Rett Syndrome (NCT00593957), a randomized phase 2 study. The primary outcome is Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm..

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, open-label, parallel-group trial of dextromethorphan in Rett syndrome. The registry record lists three dose groups: 0.25 mg/kg per day, 2.5 mg/kg/day, and 5mg/kg/day. Masking is listed as none, so the trial was not masked according to the record. The listed arms contain active dextromethorphan doses; no placebo or untreated arm is reported.

The record lists enrollment as 38 and status as terminated. The study description says the study would include 90 females and males aged 2 years to 14.99 years who had an MECP2 mutation and EEG spikes, with or without clinical seizures. These are different figures: the description's intended number and the recorded enrollment. The reason for termination is not reported in the registry record.

The recorded study start was 2004-08, and primary completion was 2010-04. The primary outcome was EEG spike counts per minute, summarized as means and standard deviations at baseline and six months. Its stated timeframe is initial and 6-month post-treatment. The primary analysis population is described as 33/35 participants who completed the protocol and had suitable non-REM sleep epochs for counting before and after dextromethorphan intake. The posted outcome summaries have group sizes of 13, 12, and 8 at both time points. Further details about randomization procedures, allocation concealment, the reason for termination, and the original statistical plan are not reported in the registry 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: Pharmacokinetics in enrolled subjects required her to be a fast metabolizer of Dextromethorphan (DM).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 33/35 participants who completed the protocol with two epochs of 5 mins of non-Rapid eye movement (REM)sleep during which spikes could be counted pre and post DM intake.

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 Difference in EEG Spike Counts at Six Months Compared to Baseline for Each Treatment Arm., measured over Initial and 6-month post-treatment.

The primary endpoint is EEG spike count, expressed as the mean number of spikes per minute. The registry describes counting spikes during two epochs of 5 minutes of non-REM sleep at baseline and six months after treatment. The outcome is intended to capture EEG spike activity, which the study description identifies as a target of the proposed dextromethorphan mechanism.

For each dose group, the posted summaries give a baseline mean and standard deviation and a six-month mean and standard deviation. A change over time in this measure can describe how the recorded EEG counts differed between the two assessment times. It does not, by itself, separate a treatment effect from other explanations for change, such as natural variation or differences between participants. The reported arms contain different doses but no separate untreated or placebo group.

General: a continuous endpoint such as a count summarized by a mean describes the average level in a group, while the standard deviation describes how dispersed individual observations are around that average. The registry reports the primary outcome as a mean measure, but does not report a full analysis plan, a prespecified clinically meaningful difference, or all participant-level observations. Results for other proposed aims, including behavior, cognition, seizures, breathing, motor capabilities, bone density, and gastrointestinal dysfunction, are not reported in the posted primary outcome results.

7. Results Posted in the Registry

• DM2 EEG Spike Counts at Baseline: mean 25.44 versus 44.22 on control; difference -18.78 (95% CI -35.44 to -2.12), standardized effect d = -0.88; z-test p = 0.027.
• DM1 EEG Spike Count at 6 Months: mean 38.29 versus 44.22 on control; difference -5.93 (95% CI -26.84 to 14.98), standardized effect d = -0.22; z-test p = 0.578.
• DM2 EEG Spike Counts at 6 Months: mean 27.58 versus 44.22 on control; difference -16.64 (95% CI -33.64 to 0.36), standardized effect d = -0.76; z-test p = 0.055.

8. Statistical Interpretation

9. Statistical Methods Explained

General: statistical methods help distinguish the size of an observed difference from the uncertainty around it. A mean describes the average of a continuous measure in a group. A standard deviation describes the spread of observations within that group; it is not the uncertainty in the mean itself. The EEG outcome is reported as mean spike counts per minute with standard deviations.

What does a mean difference represent?

A mean difference is one group mean minus a reference group mean. The recalculations use DM1 baseline as the reference. The reported differences of -18.78, -5.93, and -16.64 therefore indicate lower means in the comparison groups than in that reference group. This direction is descriptive and does not itself establish that treatment lowered counts. The first recalculated comparison is between DM2 and DM1 at baseline. The other two compare six-month means with the DM1 baseline mean. These are not three within-arm changes from baseline.

What does a confidence interval add?

General: a confidence interval gives a range of values compatible with a statistical estimate under the assumptions of the analysis. A wider interval indicates less precision than a narrower interval. An interval that includes zero is compatible with a range of possibilities that includes no mean difference, as well as differences in either direction. The recalculated intervals are based on posted summary statistics, rather than participant-level measurements or an adjusted model.

What do the p-values say?

General: a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the analysis assumptions were correct. It does not give the probability that the null hypothesis is true, and it does not measure clinical importance. The recalculated p-values are unadjusted. They do not account for the number of outcomes or analyses, and the registry record does not report a multiplicity adjustment plan.

The sponsor's analysis entries report two-sided t-tests for baseline and six-month observations within each dose group. They list p-values as <0.40, <0.62, and <0.38, respectively. These entries do not include the test estimates or interval bounds. Because the reported sponsor analysis and the recalculated comparisons differ, the sponsor's own analysis takes precedence. The recalculations are simple unadjusted comparisons derived from the posted group summaries and should not replace the sponsor's analysis.

Why does spread matter?

General: when observations vary substantially within groups, a mean can be estimated less precisely unless the group contains enough observations. Over-dispersion, in general, means that variability is larger than a statistical model assumes; it can make model-based uncertainty too small if not handled appropriately. The registry reports standard deviations but does not report an over-dispersion assessment or a model for the EEG counts. It is therefore not possible to determine from the record whether a count-specific model was considered or whether the analysis assumptions were checked.

What is not available about the analysis?

The record identifies a mean outcome, standard deviations, a timeframe, and sponsor-reported t-tests. It does not report the original statistical analysis plan, the planned handling of missing observations, the treatment of multiple outcomes, or whether the reported analysis was prespecified. It also does not report whether the analysis accounted for repeated measurements within participants. The primary population description refers to participants who completed the protocol with countable sleep epochs at both time points, but a full account of exclusions and missing outcome data is not reported in the registry record.

General: in a randomized trial, comparisons between assigned groups can support an estimate of a treatment contrast when the analysis follows the randomization and the comparison is appropriate. A baseline group difference is not a treatment contrast, and a before-and-after difference without a suitable comparison group cannot separate treatment-related change from other influences. These distinctions matter when interpreting the posted summaries and recalculations.

10. Confidence Intervals and Precision

The group means are based on modest numbers of participants: 13 in DM1, 12 in DM2, and 8 in DM3 at both baseline and six months. The primary population description refers to 33/35 participants with protocol completion and countable epochs at both assessments. The small group sizes mean that the estimates can be sensitive to the observations included, and the reported standard deviations show appreciable variation within groups.

The recalculated confidence intervals illustrate the uncertainty in the mean differences. For DM1 at six months compared with DM1 baseline, the interval runs from -26.84 to 14.98. For DM2 at six months compared with DM1 baseline, it runs from -33.64 to 0.358. Both intervals include zero and also allow for differences in either direction. For DM2 at baseline compared with DM1 baseline, the interval runs from -35.44 to -2.115. That interval describes the baseline difference between those groups; it is not evidence of a treatment-related change.

General: confidence intervals quantify statistical uncertainty under the assumptions used to calculate them. They do not account automatically for bias, missing data, design limitations, or multiple testing. The registry's sponsor-reported t-test entries do not provide interval bounds for the comparisons, and the original analysis plan is not reported. The recalculated intervals are unadjusted and based on summary statistics. Their precision should therefore be considered alongside the open-label design, the use of a baseline reference group in the recalculations, and the lack of a reported untreated comparison arm.

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 sample-size figures are planning illustrations for future comparisons, not participant counts observed in the trial. They are expressed as participants per arm, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The registry record's original design assumptions are not reported.

The 80% power column gives the number of participants per arm estimated to be needed for an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the other assumptions hold. The 90% power column gives the corresponding number for a 90% chance. These are design targets, not guarantees, and neither column describes the probability that the trial's result is true.

Each planning row uses a different fraction of the observed effect: 100%, 75%, or 50%. Smaller effects require more participants in these illustrations. The curve represents the same general planning relationship across the specified effects; its values should be read as planning estimates rather than as a reconstruction of the trial's original sample-size rationale. The illustrations use the observed effect from the recalculated comparison, which may be unstable when group sizes are small. This is 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 = -18.780; pooled standard deviation σ = 21.453.
2. n = 2 × (1.96 + 0.842)² × 21.453² / -18.780² = 20.5, rounded up to 21 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 <- -18.78                      # observed difference in means
sigma <- 21.4534022841417                     # 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(593957)
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 = 21 (80% power), 28 (90% power)
 75% of observed effect: n per arm = 37 (80% power), 49 (90% power)
 50% of observed effect: n per arm = 82 (80% power), 110 (90% power)
power.t.test: 21.5 
Simulated power at n = 21 per arm: 0.794 (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 sponsor's registry entries report two-sided t-tests comparing baseline and six-month entries within the DM1, DM2, and DM3 groups. The listed p-values are <0.40, <0.62, and <0.38. The entries do not provide test estimates or confidence interval bounds. The recalculations instead compare selected group means using DM1 baseline as the reference. For that reason, the recalculated comparisons do not reproduce the sponsor's stated within-group comparisons.

The recalculated mean differences and unadjusted p-values are -5.93 and 0.578 for DM1 at six months versus DM1 baseline; -16.64 and 0.055 for DM2 at six months versus DM1 baseline; and -18.78 and 0.027 for DM2 at baseline versus DM1 baseline. The last is a baseline group contrast, not a before-and-after treatment comparison. The registry record flags a discrepancy between the sponsor analysis and the recalculation. The sponsor's own analysis takes precedence; the recalculations are simple, unadjusted results from posted summary statistics and should be treated as a separate statistical check.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary EEG outcome and secondary outcomes concerning receptive language and SSI mean scores. It also reports multiple analyses. When several outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. General: multiplicity procedures are methods for controlling or describing this issue, for example by adjusting a decision threshold or identifying a primary comparison in advance. The registry record does not report a multiplicity plan or indicate whether p-values were adjusted.

The sponsor's reported analyses are two-sided t-tests for each dose group's baseline and six-month entries. The recalculated comparisons are unadjusted. Neither set of entries provides enough information to establish how the analyses were selected, whether they were prespecified, or how results across outcomes were handled. This limits the interpretation of individual p-values, particularly where several outcomes and analyses are listed.

The primary endpoint population is described as 33/35 participants who completed the protocol and had countable sleep epochs at both assessments. The posted arm summaries give group sizes of 13, 12, and 8 at baseline and six months. The record does not provide a full accounting of participants with missing measurements, reasons for missingness, or the method used to handle missing data. It also does not describe an intention-to-treat analysis population or another complete analysis-population definition. The original analysis plan is not reported in the registry record.

General: missingness can affect a comparison if the probability of having an observed outcome is related to participant characteristics or outcomes. Restricting an analysis to participants with complete measurements may produce results that differ from an analysis including all randomized participants, depending on why observations are missing. Without details on missingness and analysis populations, the direction and size of any such effect cannot be determined. These limitations apply to interpretation of the posted endpoint summaries and do not establish that missing data caused a particular result.

15. 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.

The serious adverse event figures list 13 participants at risk in DM1, 12 in DM2, and 10 in DM3. The number affected by a serious adverse event is recorded as 0 in each group. The registry also lists 0 participants affected by other adverse events in each group. These are counts in the posted safety entries, not estimates of risk beyond the reported groups.

The death counts are not reported in the registry record. The record does not provide serious adverse event terms, so no specific event types can be described from these entries. The safety group sizes differ from the primary outcome group sizes: DM3 has 10 participants at risk in the safety entry and 8 in the EEG summaries. The registry does not explain this difference. These figures should be read as the safety information recorded in the registry, not as a complete assessment of all possible harms or as a comparison of safety across doses.

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

The posted results describe EEG spike counts in three dextromethorphan dose groups at baseline and six months. The group means differ across time and dose, and the standard deviations indicate variation among participants. The registry also reports sponsor-conducted two-sided t-tests within dose groups, but the entries give only broad less-than p-value statements and do not provide estimates or confidence intervals. Recalculations from the group summaries provide additional unadjusted contrasts, but these use DM1 baseline as the reference rather than estimating all within-arm changes.

These results do not establish that dextromethorphan caused a change in EEG spike counts. The record lists no separate placebo or untreated group, and the open-label design means participants and study personnel were not masked. The baseline means also differ across dose groups. A lower mean in one group than another, especially at baseline, is not evidence of a treatment effect. The recalculated comparisons do not substitute for the sponsor's own analysis, which takes precedence when the two differ.

The results also do not answer every question named in the study description. Although the description mentions behavior, cognition, seizures, breathing abnormalities, motor capabilities, bone density, and gastrointestinal dysfunction, results for those measures are not reported in the posted primary outcome results. The registry lists secondary outcomes, but complete results for them are not presented in the record summarized by these endpoint data.

General: statistical uncertainty is only one part of evidence. A precise estimate can still be biased if the design or analysis does not support the intended comparison, while an imprecise estimate may be compatible with a wide range of effects. The small outcome groups, incomplete analysis details, and lack of a separate untreated comparison group constrain interpretation. The posted data describe observed summaries and reported tests; they do not by themselves establish benefit, lack of benefit, or a dose-response relationship.

17. Why This Trial Matters Statistically

This trial illustrates why the comparison being estimated matters as much as the arithmetic. Its primary outcome is framed as a baseline-to-six-month difference within each dose group, while the available recalculations compare selected groups against the DM1 baseline mean. Those are different statistical questions. A baseline contrast can describe imbalance between groups but cannot be interpreted as a treatment-related change.

The record also illustrates the importance of distinguishing sponsor-reported analyses from recalculations based on summary statistics. The sponsor reports two-sided t-tests for baseline and six-month entries within each dose group. The recalculations produce unadjusted mean differences and confidence intervals for comparisons against DM1 baseline. Because the record identifies a discrepancy, the sponsor's own analysis takes precedence, while the recalculations remain useful as a separate check on the posted summaries.

Finally, the trial's small group sizes, open-label design, reported termination, and limited information about missing data, multiplicity, and the original analysis plan make transparent statistical reporting especially important. The enrollment record and the study description's intended number also differ. These features do not determine the result, but they shape how confidently the posted statistics can answer the clinical question. The case is a reminder that estimates, uncertainty intervals, analysis populations, and the design of the comparison all need to be considered together.

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.

Several trial-specific limitations affect interpretation. The record reports enrollment of 38, while the study description says the study would include 90 participants. The registry lists the trial as terminated, but the reason for termination is not reported in the registry record. It is not possible to determine from these registry entries why enrollment differed from the number in the study description or what effect termination had on the planned analyses.

The trial was randomized but open-label, with no masking listed. All reported arms are dextromethorphan dose groups, and no separate placebo or untreated group appears in the listed arms. The recalculated contrasts use DM1 baseline as the reference, which is not a concurrent control group. The posted baseline means vary across dose groups, and the group sizes for the primary summaries are 13, 12, and 8.

The primary endpoint population is described as 33/35 participants with protocol completion and countable epochs at both time points. The record does not explain the 33/35 wording, provide a full accounting of missing observations, or describe the analysis population in further detail. The DM3 safety group has 10 participants at risk, while the EEG summaries list 8; a reason for the difference is not reported.

The original statistical analysis plan, sample-size justification, multiplicity strategy, and detailed missing-data methods are not reported in the registry record. The sponsor's analysis entries give p-values but not estimates or interval bounds. The recalculated comparisons are unadjusted and do not reproduce the sponsor's within-group analysis. Results for several clinical outcomes named in the study description are not reported among the posted primary outcome results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Trial of Dextromethorphan in Rett Syndrome — NCT00593957.
• Registry record last updated 2014-04-23; status last verified 2013-07.
• Results first posted 2014-04-23.
• 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 Phase 2, randomized, open-label, parallel-group study of three dextromethorphan doses in Rett syndrome. Enrollment is listed as 38, and the status is terminated. The primary endpoint is mean EEG spike counts per minute at baseline and six months. The outcome summaries include 13 participants in DM1, 12 in DM2, and 8 in DM3 at each time point.

The sponsor reports two-sided t-tests comparing baseline and six-month entries within each dose group. Recalculations use DM1 baseline as a reference for selected mean differences and are unadjusted; where they differ from the sponsor's analysis, the sponsor's own analysis takes precedence. The record does not report the original analysis plan, multiplicity approach, detailed missing-data methods, or reason for termination. The posted results describe the recorded data but do not establish a causal treatment effect.