Placebo Controlled Trial of Dextromethorphan in Rett Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Placebo Controlled Trial of Dextromethorphan in Rett Syndrome (NCT01520363), a randomized phase 2 study. The primary outcome is Change in Mullen; Visual Reception Sub-scale Scores, Pre- and Post-Intervention.

2. Clinical Question

The registry’s stated rationale describes increased NMDA-type glutamate receptors in the brains of young people with Rett syndrome and proposes that dextromethorphan could counter their effects. That biological rationale explains why the investigators selected the drug; it does not establish what the trial found. The outcome data are needed to assess the observed score patterns and their precision.

The primary population description notes that two noncompliant participants were removed from the study-drug group. At 3 months, 22 participants in that group and 25 in the placebo group were analyzed because of incomplete data. These details matter when interpreting the results: the reported outcome is based on the participants analyzed, rather than necessarily every participant enrolled or randomized.

3. Trial Design

This was a phase 2, randomized, parallel-group trial comparing dextromethorphan with placebo in Rett syndrome. The registry records enrollment of 57 participants and lists the study status as completed. The study began in 2012-03, and primary completion was recorded as 2016-10-26. The primary outcome timeframe was initial evaluation and the end of the 3 month trial.

The registry categorizes masking as quadruple. Its brief summary describes the study as double blinded. The record does not specify which particular roles were masked under the quadruple classification, so those details are not reported in the registry record. The intervention arms are described as mutation-positive participants randomized to dextromethorphan or placebo.

The reported primary-outcome population was narrower than the full enrollment: mutation-positive participants who were fast metabolizers at baseline. The record notes that two noncompliant participants were removed from the study-drug group and that incomplete data affected the 3-month analyses. It reports 22 analyzed in the drug group and 25 in the placebo group at that time. The registry record does not report the trial’s original sample-size justification or enough detail to establish how the recorded enrollment relates to every analysis population.

Randomization and placebo control allow a comparison between groups, while masking can reduce some forms of bias in outcome assessment and participant or study-team behavior. These are general design considerations; the record does not describe the allocation procedure or the specific masking arrangements. It also does not report enough detail about the treatment schedule or dose to describe those aspects of the protocol.

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: A total of 57 participants were consented. Of these 5 were slow metabolizers who did not meet post consent eligibility criteria.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Mutation positive participants who are fast metabolizers at baseline. 2 were noncompliant and removed from the study drug group. At 3 months 22 were analyzed in the study drug group and 25 in the placebo group due to incomplete data.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Change in Mullen; Visual Reception Sub-scale Scores, Pre- and Post-Intervention, measured over Initial evaluation and at the end of the 3 month trial.

The primary endpoint was change in the Mullen Scales of Early Learning Visual Reception subscale score from initial evaluation to the end of the 3 month trial. The subscale uses raw scores from 0 to 50, and a higher score is defined in the registry as a better outcome. Age equivalents can also be computed separately for each subscale, from 1 month to 70 months; the primary outcome recorded for this trial is the raw Visual Reception score.

Visual Reception is one component of the Mullen early-learning assessment. As a continuous score, it retains more gradation than an outcome that simply classifies participants into categories. In general, a continuous outcome can help describe both the direction and size of score differences between groups. It does not, on its own, establish how meaningful a particular difference is to participants or families.

The endpoint is relevant to the investigators’ stated interest in learning and development in Rett syndrome. The trial’s description gives a higher score as better, which helps orient interpretation of the score scale. Still, the registry record does not report a threshold for a clinically meaningful difference, nor does it report validation details that would allow the numerical difference to be translated into a change in daily functioning.

The record’s primary-outcome description is framed as change over time. The sponsor’s registered primary analysis reports a net mean difference, whereas the posted arm summaries also present mean values at the initial evaluation and at 3 months. These summaries and the sponsor’s net-change analysis are related but are not interchangeable descriptions of the same contrast.

7. Results Posted in the Registry

• Study Drug-dextromethorphan (DM): mean 5.45 versus 6.61 on control; difference -1.16 (95% CI -3.94 to 1.62), standardized effect d = -0.23; z-test p = 0.414.
• Study Drug Group at 3 Months: mean 6.64 versus 6.61 on control; difference 0.03 (95% CI -3.81 to 3.87), standardized effect d = 0.00; z-test p = 0.988.
• Placebo at 3 Months: mean 6.57 versus 6.61 on control; difference -0.04 (95% CI -3.16 to 3.08), standardized effect d = -0.01; z-test p = 0.980.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change in VABS: Motor Skills Domain Scores, Pre- and Post-Intervention

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Study Drug-dextromethorphan (DM): mean 9.86 versus 11.36 on control; difference -1.50 (95% CI -3.91 to 0.91), standardized effect d = -0.34; z-test p = 0.222.
  • Study Drug-dextromethorphan (DM) at 3 Months: mean 9.64 versus 11.36 on control; difference -1.72 (95% CI -4.21 to 0.77), standardized effect d = -0.39; z-test p = 0.176.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) at 3 Months and the control. The interval gives the range of effects that remain compatible with the data.

Change in VABS:Daily Living Skills Domain Scores, Pre- and Post-Intervention

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Study Drug-dextromethorphan (DM): mean 21.64 versus 21.00 on control; difference 0.64 (95% CI -2.81 to 4.09), standardized effect d = 0.10; z-test p = 0.716.
  • Study Drug-dextromethorphan (DM) at 3 Months: mean 20.95 versus 21.00 on control; difference -0.05 (95% CI -3.41 to 3.31), standardized effect d = -0.01; z-test p = 0.977.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) at 3 Months and the control. The interval gives the range of effects that remain compatible with the data.

Change in VABS: Socialization Domain Scores, Pre- and Post-Intervention

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Study Drug-dextromethorphan (DM): mean 24.14 versus 22.96 on control; difference 1.18 (95% CI -1.75 to 4.11), standardized effect d = 0.22; z-test p = 0.429.
  • Study Drug-dextromethorphan (DM) at 3 Months: mean 24.05 versus 22.96 on control; difference 1.09 (95% CI -2.23 to 4.41), standardized effect d = 0.19; z-test p = 0.520.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Drug-dextromethorphan (DM) at 3 Months and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes covering VABS motor skills, daily living skills, socialization, and communication, as well as social interaction and Rett Syndrome Behavior Questionnaire scores. Quantitative arm summaries and analyses are present for motor skills, daily living skills, and socialization. Results for the other listed secondary outcomes are not reported in the registry record in the same set of summaries.

Across the secondary outcomes with posted quantitative analyses, the sponsor’s reported results include estimates in differing directions and p-values that are not uniformly small. One placebo comparison for daily living skills is recorded with a p-value of <0.005, while other reported secondary comparisons have larger p-values. The unadjusted recalculations are also not uniformly suggestive of a group difference. These results should not be collapsed into a single conclusion about all secondary outcomes.

The secondary outcomes add context to the primary result by addressing other areas of function and behavior, but they do not override the primary analysis. They are separate measures, with potentially different scales and analysis populations. A result on one secondary measure does not establish a corresponding effect on the Mullen Visual Reception endpoint.

The registry records 17 outcome measures and 30 analyses. It does not report whether a multiplicity adjustment was planned or applied. In general, when many outcomes or tests are examined, the chance of at least one apparently notable finding can increase. Therefore, an isolated unadjusted secondary result carries less weight than a prespecified primary analysis, especially when the broader pattern is mixed and the analysis plan is not fully reported. The secondary findings are best treated as exploratory signals requiring cautious interpretation, not as independent confirmation of the primary result.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change in VABS: Motor Skills Domain Scores, Pre- and Post-Intervention
• Change in VABS:Daily Living Skills Domain Scores, Pre- and Post-Intervention
• Change in VABS: Socialization Domain Scores, Pre- and Post-Intervention
• Change in VABS:Communication Domain Scores, Pre- and Post-Intervention
• Change in Ghuman-Folstein Screen for Social Interaction (SSI) Score, Pre- and Post-Intervention.
• Change in Rett Syndrome Behavior Questionnaire Score, Pre- and Post-Intervention

9. Statistical Interpretation

10. Statistical Methods Explained

For a continuous outcome such as the Mullen Visual Reception score, a mean describes the arithmetic average of participants’ scores in a group. The registry reports means and standard deviations for the arms. A standard deviation describes how spread out individual scores are around their group mean; it is not the uncertainty in the mean itself. General distinction: variability among participants and uncertainty about an estimated group contrast are related but different quantities.

What does a mean difference represent?

A mean difference subtracts one group’s mean from another group’s mean, with the direction depending on the comparison order. The sponsor’s primary result is reported as a net mean difference of -1.182. The registry does not give a more detailed definition of the sponsor’s net calculation in the outcome record. The unadjusted recalculations use posted summary statistics and are not adjusted analyses. They compare the initial group means and, separately, the 3-month group means.

For the initial values, the recalculated mean difference is -1.16, with a 95% confidence interval from -3.944 to 1.624 and an unadjusted p-value of 0.414. For the 3-month values, the recalculated difference is 0.03, with a 95% confidence interval from -3.813 to 3.873 and an unadjusted p-value of 0.988. These calculations are descriptive comparisons from posted summaries. They do not replace the sponsor’s registered net-change analysis.

How should a confidence interval be understood?

In general, a confidence interval is a range of values that expresses uncertainty around an estimated effect under the method used to calculate it. It is not a range containing a fixed percentage of individual participants’ scores, and it is not a guarantee that the true effect falls inside the interval. A wider interval indicates less precision than a narrower interval, all else being equal. The sponsor’s 95% interval for the primary result runs from -3.086 to .722. Because it includes zero, the data do not distinguish the estimated net difference from zero at the usual two-sided 0.05 threshold. The interval’s width also means the estimate is not highly precise.

What does a p-value add?

In general, a p-value measures how inconsistent the observed result is with a specified null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, nor is it a measure of clinical importance. The sponsor reports p = .211 for the primary net comparison. The recalculated p-values are unadjusted and should be read as descriptions of those specific simple comparisons, not as replacements for the trial’s analysis plan. The registry record does not report a complete statistical analysis plan that would define every planned test or adjustment.

The registry labels the sponsor’s primary analysis as a two-sided t-test and reports a mean difference. A t-test is a general method for comparing means while accounting for sampling variation. The sponsor also reports an analysis of placebo final values using a median difference. A median describes the middle of an ordered set of values; it is not the same summary as a mean. The available registry record does not give enough detail to reconcile every estimator and analysis population beyond the labels and results recorded.

What do the recalculations represent?

The recalculated estimates are simple, unadjusted calculations from posted group summary statistics. They use the means, standard deviations, and sample sizes recorded for the relevant arms. They do not account for covariates, repeated measurements, missing-data mechanisms, or any other adjustment unless that adjustment is explicitly included in the recorded summary statistics; such adjustments are not part of these recalculations. The sponsor’s reported analysis remains the trial’s own analysis and is presented separately.

General caution: a change score, an end-of-study score, and a comparison of means at a single time point answer different statistical questions. The primary outcome is described as change from initial evaluation to the end of the trial. The posted summaries give values for the initial evaluation and at 3 months, while the sponsor reports a net mean difference. Readers should not infer that a simple end-point comparison reproduces a change-score analysis.

11. Confidence Intervals and Precision

The sponsor’s registered primary estimate is a net mean difference of -1.182, with a 95% confidence interval from -3.086 to .722. The interval crosses zero, so the estimate does not pin down a single direction of difference. It includes values on both sides of zero, and therefore allows for a range of effects consistent with the reported data and method. Its p-value is .211.

In general, a confidence interval communicates precision as well as direction. A narrow interval would indicate a more tightly estimated contrast, while a wide interval leaves more uncertainty about the effect’s size. The primary interval is broad relative to the point estimate and includes both negative and positive values. It does not establish that the groups are identical; a non-significant result is not proof of no difference.

The unadjusted recalculated intervals are also wide. For the initial means, the difference is -1.16, with an interval from -3.944 to 1.624. For the 3-month means, it is 0.03, with an interval from -3.813 to 3.873. These intervals concern the respective simple comparisons and are not estimates of the sponsor’s net-change contrast.

The observed analysis groups were small: the primary population description gives 24 participants in the study-drug group and 26 in the placebo group at initial evaluation, with 22 and 25 analyzed at 3 months. The confidence intervals reflect the uncertainty associated with the particular estimates, but they do not account for every possible source of bias or uncertainty. The registry record does not report a clinically meaningful difference threshold, so interval bounds cannot be classified against such a threshold.

12. 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 expressed as participants per arm, not total event counts. They use the observed effect as a starting point and show planning for 100%, 75%, or 50% of that observed effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column means the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding planning target for a 90% chance. These are design calculations, not observed power, and they do not describe what the completed trial achieved.

Smaller target effects require more participants to distinguish them from random variation under otherwise similar assumptions. This is why planning for 75% or 50% of an observed effect generally calls for more participants per arm than planning for the full observed effect. The plotted curve should be read as a visual representation of these planning relationships, not as evidence that a particular sample size was used or that the original protocol relied on these calculations.

These illustrations are sensitive to the observed effect used as their starting point. When an estimated effect is very small, the resulting participant counts can become extremely large. Such figures should not be treated as a recommendation or as a reconstruction of the trial’s design. The registry record does not report the original sample-size rationale.

13. 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 = -1.160; pooled standard deviation σ = 5.131.
2. n = 2 × (1.96 + 0.842)² × 5.131² / -1.160² = 307.1, rounded up to 308 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 <- -1.16                      # observed difference in means
sigma <- 5.13085337078541                     # 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(1520363)
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 = 308 (80% power), 412 (90% power)
 75% of observed effect: n per arm = 546 (80% power), 731 (90% power)
 50% of observed effect: n per arm = 1,229 (80% power), 1,645 (90% power)
power.t.test: 308.1 
Simulated power at n = 308 per arm: 0.795 (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.

14. Analyses Reported by the Sponsor

The sponsor’s registered primary analysis is a two-sided t-test reporting a net mean difference of -1.182, a 95% confidence interval from -3.086 to .722, and p = .211. This is the trial’s own reported result for the primary outcome and should be distinguished from the simple unadjusted recalculations based on posted arm summaries.

The recalculated initial-value comparison is -1.16, with a 95% interval from -3.944 to 1.624; the 3-month comparison is 0.03, with an interval from -3.813 to 3.873. Those calculations compare means at the recorded time points. They are not a reproduction of the sponsor’s net-change estimator, and differences between them should not be treated as an inconsistency without matching the estimand, analysis population, and method.

The registry also records a placebo-group analysis of median difference in final values: .043, with a 95% confidence interval from -1.345 to 1.432 and p = .949. This uses a different summary measure from the primary mean analysis. The record does not provide enough methodological detail to explain all choices behind the sponsor’s analyses. The discrepancy indicator is false, but that does not mean the different summaries estimate precisely the same quantity.

15. Multiplicity, Missing Data and Analysis Populations

The registry records 17 outcome measures and 30 analyses, including the primary outcome and a range of secondary measures. It does not report whether the investigators specified a hierarchy among secondary outcomes, planned a multiplicity adjustment, or adjusted p-values for the number of comparisons. Those procedures are not reported in the registry record, so the extent to which the analyses were confirmatory versus exploratory cannot be established from the recorded results alone.

In general, testing many outcomes increases the opportunity to observe at least one small p-value by chance, even when no underlying effects are present. Multiplicity procedures can help control that issue, but the appropriate method depends on the design and analysis plan. An unadjusted secondary p-value should therefore be interpreted cautiously when the number and relationship of tests are not clearly described.

Missing data are relevant to the primary result. The record says two noncompliant participants were removed from the study-drug group and that incomplete data led to analysis of 22 study-drug participants and 25 placebo participants at 3 months. The initial-evaluation arm summaries list 24 and 26 participants. The registry record does not report the reasons for each incomplete observation, the assumptions used to handle missing values, or sensitivity analyses assessing their impact.

The primary population is described as mutation-positive participants who were fast metabolizers at baseline. The registry record does not report a complete analysis-population definition for every outcome or whether all randomized participants were included in each analysis. Nor does it report the detailed statistical analysis plan, interim analyses, or a complete account of how multiple testing and missingness were addressed. These omissions limit how fully the registered results can be assessed, without implying that any particular procedure was or was not used.

16. 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.

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events among 26 participants at risk in the study-drug group and zero among 26 at risk in the placebo group. At the 3-month entries, it reports zero serious adverse events among 24 at risk in the study-drug group and zero among 26 at risk in the placebo group. Deaths are recorded as zero in each group.

These are counts within the recorded groups and at-risk populations. They do not show that serious adverse events are impossible, and they should not be interpreted as proof of no safety risk. In general, when event counts are zero, the data still allow uncertainty about the event rate, especially when the number observed is limited.

The record also lists other adverse events affecting 18 participants in the study-drug group at 3 months and 22 in the placebo group at 3 months. The serious-event fields are distinct from those other-event counts. The registry lists no top serious adverse-event terms. It does not report enough detail to describe event types, timing, severity grading for other events, or the method used to collect adverse events.

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

The results describe a randomized, placebo-controlled comparison of dextromethorphan and placebo on the Mullen Visual Reception score over a 3 month trial. The sponsor’s primary analysis estimates a net mean difference of -1.182, with a 95% confidence interval from -3.086 to .722 and p = .211. The interval includes zero and is not narrow enough to identify a precise difference. This is evidence about the observed data under the reported analysis, not a definitive statement about every possible effect.

The score description says higher values are better, but the registry does not state a threshold for a clinically meaningful change. Statistical estimates therefore cannot be translated into a claim about the size of benefit or harm that would matter to participants. The registered analysis also should not be replaced by a comparison of the means at a single time point; those are different contrasts.

The trial’s stated biological rationale concerns glutamate and NMDA receptors, and the proposed action of dextromethorphan. That rationale does not establish that the intervention improves symptoms or learning. The recorded efficacy outcome and its uncertainty are the relevant basis for describing what this trial found.

Likewise, the absence of recorded serious adverse events in the listed groups does not prove that no serious event can occur. The safety counts are limited to the populations and entries recorded, and the registry record does not provide all details needed to characterize safety comprehensively.

The trial should be read as one study with a particular population, outcome, duration, and set of analyses. Its results do not establish effects in populations or circumstances not represented in the record. The information does not justify medical advice or a broad claim that dextromethorphan does or does not work for Rett syndrome.

18. Why This Trial Matters Statistically

This trial illustrates why a reported point estimate should be read together with its confidence interval. The sponsor’s primary estimate is negative, but the 95% interval extends from -3.086 to .722 and includes zero. A point estimate alone would hide the uncertainty about the direction and size of the contrast. The interval helps show that the primary result is not a precise estimate.

It also illustrates the importance of identifying the exact comparison. The registered primary analysis reports a net mean difference, while the posted arm summaries include values at initial evaluation and at 3 months. A simple comparison at either time point is not the same as a net-change analysis. Statistical interpretation depends on matching the estimate to the clinical question.

Sample-size illustrations based on observed effects can also be misleading if read as the trial’s original design or as evidence of what the trial could prove. The registry’s original sample-size rationale is not reported. The illustrations are planning tools under stated assumptions, not observed power and not a reconstruction of the protocol.

Finally, the record shows how analysis populations, incomplete data, multiple outcomes, and a limited set of reported analyses shape interpretation. The primary follow-up analysis includes fewer participants than the initial group summaries, and the registry records many outcome measures and analyses without reporting a multiplicity plan. Recognizing these features is central to cautious reading of clinical-trial statistics.

19. 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 analysis population is described as mutation-positive participants who were fast metabolizers at baseline, limiting direct interpretation to that defined group. The trial enrolled 57 participants, while the primary summaries report 24 and 26 participants at initial evaluation and 22 and 25 at 3 months. The record attributes the follow-up analysis counts to incomplete data and notes that two noncompliant participants were removed from the study-drug group. The reasons and handling of all missing observations are not reported in the registry record.

The trial duration for the primary endpoint was 3 months. The registry record does not report longer-term primary outcome results, so the posted endpoint does not describe persistence of any score pattern beyond that timeframe. The original sample-size justification is also not reported, and the planning illustrations based on observed effects cannot substitute for it.

The primary outcome is a raw score on a scale from 0 to 50, with higher scores defined as better. A clinically meaningful difference threshold is not reported in the registry record. The interpretation of the numerical estimate is therefore limited to the scale and statistical uncertainty, rather than a defined threshold of practical importance.

There are 17 outcome measures and 30 analyses recorded, but the registry record does not report a full multiplicity strategy or complete statistical analysis plan. It also does not provide detailed information about the allocation procedure, masking roles, missing-data assumptions, or sensitivity analyses. These reporting limits make it difficult to assess all analytic decisions and the robustness of every result.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Placebo Controlled Trial of Dextromethorphan in Rett Syndrome — NCT01520363.
• Registry record last updated 2018-12-04; status last verified 2018-11.
• Results first posted 2018-10-23.
• 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.

23. Record Summary

The registry record describes a completed phase 2 randomized, parallel-group, placebo-controlled trial of dextromethorphan in Rett syndrome, with quadruple masking listed. Enrollment was 57. The primary endpoint was change in Mullen Visual Reception subscale scores from initial evaluation to the end of the 3 month trial.

The sponsor reported a net mean difference of -1.182, with a 95% confidence interval from -3.086 to .722 and p = .211. The interval includes zero and reflects uncertainty about the size and direction of the difference. The record also reports secondary outcomes and adverse-event counts, including zero serious adverse events in the listed groups.

Interpretation is limited by incomplete 3-month data, the specified primary analysis population, and missing details about the original design assumptions, multiplicity, and missing-data methods. The posted results describe this trial’s recorded analyses and do not establish a broader treatment conclusion.