A Trial of Levodopa in Angelman Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial of Levodopa in Angelman Syndrome (NCT01281475), a randomized phase 2, phase 3 study. The primary outcome is Bayley Cognitive Age Equivalent at 1 Year.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, placebo-controlled, parallel-group trial with quadruple masking. Its official title calls it a Phase 2 trial, while the phase classifications in the registry include Phase 2 and Phase 3. The record lists an enrollment of 67 and a completed status. The recorded study start is 2011-01, and primary completion is listed as 2015-07.

Participants were assigned to levodopa or placebo. The levodopa regimen was levodopa/carbidopa at a 4:1 ratio, with a stated dose of 15 mg/kg/day divided into 3 doses. The placebo capsule contained similar excipients but did not contain levodopa or carbidopa. The registry’s masking classification is quadruple; the identities of the masked roles are not reported in the registry record.

The primary outcome was Bayley Cognitive Age Equivalent at 1 Year, assessed at 12 months. The registry reports mean and standard deviation summaries for the two groups. The posted outcome summaries include 29 participants in the levodopa group and 26 in the placebo group. These are the group counts accompanying the primary outcome, not a description of the analysis population or an explanation for any difference between those counts and enrollment.

Presence of tremors was listed as a secondary outcome at 1 year. The registry does not report the detailed allocation procedures, eligibility criteria, baseline characteristics, adherence, or reasons for missing outcome observations. Those details should not be inferred from the randomized design or the outcome counts.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

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

Population: Only participants who completed the study were analyzed. Therefore all numbers in the Results section refer to the participants who completed the study.

6. Primary Endpoint

The registry lists the primary outcome as Bayley Cognitive Age Equivalent at 1 Year, measured over 12 months.

Bayley Cognitive Age Equivalent at 1 Year is the primary endpoint. The registry records it as a continuous measure with units of months, summarized by a mean and standard deviation, and gives its timeframe as 12 months. In plain terms, the endpoint expresses the recorded cognitive age equivalent on a months scale. It is a specific measure of the cognitive-development aspect of the trial’s broader interest in development.

Continuous measurements retain more gradation than a simple event count or yes/no outcome. Comparing group means therefore describes the average recorded score in each group, while the standard deviations describe how spread out the individual scores were within each group. Neither summary alone describes every participant’s outcome or the full distribution of scores.

Using a defined endpoint and timeframe makes the group comparison explicit: the question is whether the average Bayley Cognitive Age Equivalent differed between the levodopa and placebo groups at the recorded assessment time. The registry record does not provide further information about the assessment procedure, how the measure was administered, or how its results were interpreted clinically. Those aspects cannot be filled in from the group summaries.

7. Results Posted in the Registry

• Levodopa: mean 19.00 versus 19.00 on control; difference 0.00 (95% CI -3.99 to 3.99), standardized effect d = 0.00; z-test p = 1.000.

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.

Presence of Tremors

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Levodopa: 48.3% (14/29) versus 46.2% (12/26) on control; risk difference 2.1 percentage points (95% CI -24.3 to 28.5), risk ratio 1.05 (0.60–1.83); unadjusted two-proportion z-test p = 0.875.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levodopa and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcome listed in the registry is presence of tremors at 1 year. It addresses a different aspect of the study’s stated interest from the primary cognitive age-equivalent measure. The posted results therefore add another outcome perspective, but they do not change what the primary endpoint measures or how its mean difference should be interpreted.

Across primary and secondary outcomes, the registry presents distinct outcome types and analyses: a continuous primary measure and a binary secondary measure. They are not interchangeable, and a pattern across them should not be treated as though it were a single combined endpoint. The record does not report a prespecified method for combining these outcomes or a hierarchy explaining how they were to contribute to an overall conclusion.

Unadjusted secondary results generally carry less inferential weight when many outcomes or comparisons may be examined, because the chance of finding an apparently notable result can increase with repeated testing. This is a general statistical concern, not evidence that a particular adjustment was required or performed in this trial. Multiplicity procedures are not reported in the registry record. The secondary outcome should thus be considered alongside its uncertainty and the status of the analysis plan, rather than interpreted in isolation as definitive confirmation or contradiction of the primary comparison.

The record includes a planning illustration tied to the observed secondary effect and specified assumptions. Such planning figures describe hypothetical future sample sizes under those assumptions; they are not evidence that the current study had a particular probability of detecting an effect. The registry record does not report the trial’s original sample-size justification or whether the secondary outcome was intended to support a confirmatory claim.

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

• Presence of Tremors

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the main descriptive quantities are the mean and standard deviation in each group. A mean represents the arithmetic average of the recorded outcome values. A standard deviation describes their spread around that average. The registry reports means of 19.0 months in both groups, with standard deviations of 7.0 months for levodopa and 8.0 months for placebo.

What does the mean difference represent?

The mean difference places the groups on a common scale by subtracting one group’s mean from the other’s. The recalculated unadjusted difference is 0.0 months. A value of zero corresponds to equal group means; a positive or negative value would indicate a difference in one direction or the other according to the comparison’s ordering. This is a group-level contrast and does not indicate that individual outcomes were identical.

What is an unadjusted comparison?

In general, an unadjusted comparison uses the available group summaries without accounting for additional covariates or features of the design in a model. The posted recalculation uses the group means and standard deviations for the primary outcome. Its standard errors are 1.3 for levodopa and 1.569 for placebo, and the pooled standard deviation is 7.488. The recalculated confidence interval is -3.993 to 3.993 months, with an unadjusted p-value of 1.0. The registry record does not report that this simple comparison was the sponsor’s prespecified primary analysis.

What does the sponsor’s method mean?

The sponsor reports generalized estimating equations, or GEE, for the primary comparison and gives a p-value of 0.75. In general, GEE is a regression approach often used when observations may be correlated, such as repeated observations from the same participant. The registry record does not state the model formula, correlation structure, covariates, outcome handling, or other implementation details. It is therefore not possible to determine from the record exactly how the GEE analysis was specified or how its result relates numerically to a particular model estimate.

The recalculated comparison and the GEE analysis should not be treated as interchangeable. The recalculation is an unadjusted comparison based on posted summary statistics; the sponsor’s analysis is the reported analysis method. The registry does not flag a discrepancy between them. The sponsor’s reported analysis remains the relevant account of the sponsor’s own statistical analysis, while the recalculation helps describe the posted summaries in a direct, unadjusted way.

How should a p-value be read?

In general, a p-value describes how unusual data at least as incompatible with a null hypothesis would be under that hypothesis and the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it is not a measure of the size of a difference. A p-value also does not establish clinical importance. The unadjusted p-value of 1.0 accompanies an estimated mean difference of 0.0 months; the sponsor’s reported p-value is 0.75 under its GEE analysis.

Why can modeling choices matter?

In general, an adjusted or correlated-data model can account for features that a simple summary comparison does not, but its interpretation depends on the model specification and data used. Details of the sponsor’s model are not reported in the registry record. The primary outcome summaries also do not disclose how missing observations were handled or which analysis population was used. Those omissions limit an independent assessment of the sponsor’s modeling choices.

What is over-dispersion?

In general, over-dispersion occurs when the observed variability in data exceeds what a chosen statistical model assumes. It can affect uncertainty estimates and inference for outcomes such as counts or binary events. It is not a reported issue for the primary continuous outcome in this record, and there is no basis to assert that over-dispersion was present or assessed. The general concept does not alter the interpretation of the posted mean and standard deviation summaries.

The registry also includes planning illustrations for the secondary binary outcome. Such figures are prospective planning calculations based on stated assumptions and fractions of the observed effect; they are not observed power and do not describe the trial’s original design justification. The record states assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. The trial’s own sample-size justification is not reported in the registry record.

11. Confidence Intervals and Precision

Precision is about how narrowly the data estimate a group contrast, not whether a result is important. For the primary outcome, the recalculated mean difference is 0.0 months, and its confidence interval extends from -3.993 to 3.993 months. The interval includes no difference and spans values on either side of it. This conveys uncertainty that is not captured by the point estimate alone.

In general, a confidence interval is a range produced by a statistical procedure that, under its assumptions, is designed to cover the underlying parameter at a stated long-run frequency. It is not a range containing a known proportion of individual participant outcomes, and it is not a guarantee that the true effect lies within the particular interval. The confidence level for the recalculated interval is not separately stated in the registry record, so it should not be inferred from the interval alone.

The group standard deviations, 7.0 months and 8.0 months, show that individual values varied within both groups. The outcome counts accompanying the primary summaries are 29 for levodopa and 26 for placebo. The registry record does not explain the relationship between these outcome counts and enrollment, or report whether missing outcome data were present and how they were handled.

The interval is specific to the unadjusted recalculation from the posted summary statistics. The sponsor’s GEE analysis has a reported p-value of 0.75, but a sponsor-reported confidence interval is not reported in the registry record. Because the model details are also absent, the sponsor’s estimate and precision cannot be independently reconstructed from the record. Precision should therefore be discussed separately for the recalculated contrast and the sponsor’s reported test.

12. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis is a generalized estimating equations analysis with a superiority comparison and p=0.75. The registry record does not give an estimate, confidence interval, or further model details for that analysis. It therefore supports reporting the sponsor’s method and p-value, but not reconstructing the complete model-based result.

The unadjusted recalculation from the posted group summaries gives an estimated mean difference of 0.0 months, a confidence interval from -3.993 to 3.993 months, and an unadjusted p-value of 1.0. This recalculation is a simple comparison of the reported means and standard deviations. It is not a replacement for the sponsor’s GEE analysis, which may incorporate features not represented in the summary-statistic calculation; the registry record does not say which features were used.

The record does not flag a discrepancy between the recalculation and the sponsor’s own analysis. Their p-values are not identical, but they arise from differently described analyses and should not be compared as though they were outputs of one method. The sponsor’s analysis is the record of the sponsor’s inferential approach; the recalculation supplies a transparent, unadjusted reading of the posted summaries. Both should be interpreted with the limitations of the registry record in view.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome and one posted secondary outcome. It does not report a multiplicity adjustment, a testing hierarchy, or a prespecified strategy for controlling the chance of false-positive findings across outcomes. This absence does not establish that no such plan existed; it means the plan is not reported in the registry record. As a result, secondary p-values should be read as unadjusted findings unless an adjustment is explicitly documented.

Multiplicity matters in general because examining several outcomes or comparisons creates multiple opportunities for a result to appear noteworthy by chance. Whether adjustment is appropriate depends on the objectives and prespecified analysis strategy. The registry does not provide enough detail to determine the planned family of hypotheses, whether interim testing occurred, or how any multiplicity was handled.

Missing-data procedures are also not reported in the registry record. The record does not explain how incomplete assessments were treated, whether imputation was used, or whether sensitivity analyses were conducted. The outcome counts accompanying the primary summaries are not, by themselves, an explanation of missingness. Nor do they identify the analysis population.

The record does not state whether the primary analysis followed an intention-to-treat principle, included participants according to treatment received, or used another population definition. The relevant analysis populations and exclusions are not reported in the registry record. Without those details, it is not possible to assess the extent to which the analysis preserved the randomized comparison or how exclusions might affect the result.

Interim analyses and stopping rules are not reported in the registry record. The record also does not provide a detailed statistical analysis plan or the full specification of the sponsor’s GEE model. These gaps constrain evaluation of the analysis process; they do not, on their own, show that a particular procedure was omitted.

14. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: seizure (6.1%), vomiting (3.0%), fever (2.9%).

The registry reports serious adverse events affecting 3 participants in the levodopa group among 33 at risk, and 1 participant in the placebo group among 34 at risk. It also reports other adverse events affecting 11 participants among 33 at risk in the levodopa group and 9 among 34 at risk in the placebo group. These are the registry’s group-level counts and should be read with their stated at-risk denominators.

The serious adverse event terms listed with percentages are Seizure at 6.1%, Vomiting at 3.0%, and Fever at 2.9%. The record does not specify in this listing how the terms are distributed by group or provide further event-level detail. The percentages should not be assigned to a treatment group without that information.

Deaths are not reported in the registry record. The adverse-event summaries do not provide timing, severity grading beyond the serious-event classification, duration, relatedness assessments, or details about repeat events. Counts of participants affected are not the same as counts of all events if an individual could have experienced more than one event; the record does not clarify that distinction. These summaries describe safety reporting and do not establish a causal relationship between an intervention and an event.

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

The primary result describes similar reported group averages for Bayley Cognitive Age Equivalent at 12 months: both means are 19.0 months. The unadjusted recalculation estimates a mean difference of 0.0 months, with a confidence interval from -3.993 to 3.993 months. This captures the observed summaries and the uncertainty of that particular comparison.

It does not establish that the groups had identical outcomes, since the standard deviations show variability within each group. It also does not establish that all possible differences are absent: the confidence interval includes differences in both directions. Nor does the result, by itself, establish clinical importance. The registry record does not provide a threshold for a clinically meaningful change on this endpoint.

The reported primary outcome is narrower than the trial’s broad interest in development. The result applies to the named cognitive age-equivalent measure at the recorded timepoint; it should not be generalized automatically to every aspect of development, tremor, or other outcomes. The separate secondary outcome has its own measurement and uncertainty, and cannot substitute for the primary endpoint.

These findings should not be interpreted as medical advice or as a general statement about levodopa. A registry summary is limited to the outcomes and analyses it records. Detailed information about baseline characteristics, eligibility, adherence, missing data, analysis populations, and the GEE model is not reported in the registry record. Those omissions limit broader interpretation and prevent a complete independent reconstruction of the sponsor’s analysis.

In statistical terms, the most defensible reading is descriptive: the posted primary means are equal at the reported precision, and the unadjusted interval indicates uncertainty around the group contrast. The sponsor separately reports a GEE p-value of 0.75. These results should be understood as evidence from this trial record, not as a universal conclusion about outcomes in all children with Angelman syndrome.

16. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between a point estimate and its uncertainty. The primary means are both 19.0 months, giving a recalculated difference of 0.0 months, while the confidence interval extends from -3.993 to 3.993 months. Reporting the interval alongside the estimate makes clear that the analysis is not simply a declaration of equality: it also communicates the range of values compatible with the unadjusted summary comparison.

It also illustrates why the reported analysis and a transparent recalculation should be distinguished. The registry gives a GEE method and p=0.75, while the summary-statistic recalculation gives an unadjusted p-value of 1.0. Different analytic approaches can produce different inferential summaries without making the descriptive group means different. The model details would be needed to evaluate the sponsor’s estimate and uncertainty more fully.

The trial record also demonstrates the importance of clear reporting beyond a headline result. Details about missing data, analysis populations, multiplicity, interim analyses, and the original sample-size rationale are not reported in the registry record. These are important for judging how a trial’s statistical conclusions were planned and how robustly they can be interpreted.

Finally, the secondary outcome and its planning illustration show why outcome-specific interpretation matters. A secondary binary outcome is not interchangeable with a continuous primary endpoint, and planning calculations based on an observed effect are not observed power. Separating description, inference, precision, and planning helps readers avoid giving any single statistic more meaning than it supports.

17. 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 follow from the amount of information reported in the registry. The primary outcome summaries give group means, standard deviations, and outcome counts, but baseline characteristics and eligibility details are not reported in the registry record. Without them, the reader cannot assess the clinical composition of the groups or the context for the recorded scores.

The sponsor’s GEE analysis is named, but its model specification is not reported in the registry record. Covariates, correlation structure, analysis population, and treatment of incomplete observations are not described. Consequently, the sponsor’s model-based estimate and confidence interval cannot be reconstructed from the record. The unadjusted recalculation remains a separate summary-based analysis, not a substitute for those missing details.

The record does not report the original sample-size justification, a detailed analysis plan, multiplicity procedures, interim analyses, adherence, or reasons for missing outcome data. It also does not state how the primary measure was administered or define a threshold for clinical importance. These omissions limit assessment of prespecification, robustness, and practical interpretation.

Safety information is presented as group counts and a short list of serious-event terms. Further detail about event timing, relatedness, severity, recurrence, and treatment group for the listed terms is not reported in the registry record. The available summaries therefore support a bounded description of reported events, not a complete evaluation of their context or cause.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Trial of Levodopa in Angelman Syndrome — NCT01281475.
• Registry record last updated 2020-07-15; status last verified 2020-07.
• Results first posted 2017-01-13.
• 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.

21. Record Summary

The registry record describes a completed randomized, placebo-controlled, parallel-group trial with quadruple masking. It lists an enrollment of 67, a study start of 2011-01, and primary completion in 2015-07. The official title identifies a Phase 2 trial; the registry phase classifications include Phase 2 and Phase 3.

The primary endpoint was Bayley Cognitive Age Equivalent at 1 Year, measured in months at 12 months. The posted group means were 19.0 months for levodopa and 19.0 months for placebo. The unadjusted recalculation gives a mean difference of 0.0 months, a confidence interval from -3.993 to 3.993 months, and an unadjusted p-value of 1.0. The sponsor reports a GEE superiority analysis with p=0.75.

Presence of tremors was listed as a secondary outcome. The record also reports adverse-event summaries and limited serious-event terms. Details about missing data, analysis populations, the complete statistical plan, and the sponsor model specification are not reported in the registry record.