Sildenafil for the Treatment of Lymphatic Malformations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sildenafil for the Treatment of Lymphatic Malformations (NCT02335242), a randomized phase 2 study. The primary outcome is Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination..

2. Clinical Question

3. Trial Design

This was a Phase 2 randomized, parallel-group study sponsored by Stanford University. The registry lists enrollment of 22 and a completed status. The recorded start date is 2015-05-23, and the primary completion date is 2021-03-30. The brief description calls it a 32-week study, while the primary endpoint is measured from baseline to week 20 and its description gives an expected average follow-up of 20 weeks. These are different timing descriptions in the record; the registry does not explain the relationship between them.

The study included double-blind placebo, double-blind sildenafil, and open-label sildenafil groups in the posted primary endpoint results. The registry’s design fields identify randomized allocation, a parallel model, and quadruple masking. Its brief description says treatment assignment was randomized in a double-blind fashion. The record does not describe the practical masking arrangements or explain the difference in masking terminology, so the exact roles masked should not be inferred.

The brief description says placebo recipients could receive an open-label extension. The posted summaries distinguish the blinded sildenafil group from the open-label sildenafil group, but do not give the sequence or timing for each person. The summaries report 7 participants in the double-blind placebo group, 10 in the double-blind sildenafil group, and 6 in the open-label sildenafil group for the primary endpoint. The open-label results are descriptive and do not have the same blinded comparison context as the placebo-controlled results.

The stated funding source is FDA OOPD. The registry record does not report further details about allocation procedures, treatment adherence, protocol deviations, or the statistical plan.

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: 78 individuals were assessed for eligibility; 22 were enrolled, and 19 were randomized to a study arm.

Randomized Phase (20 Weeks)

Reasons for not completing this period:

Open-label Phase (20 Weeks)

Follow-up Period (12 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who completed each treatment period are included in the analysis

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 Lesion Volume of the Test Medication as Evaluated by MRI Examination., measured over Baseline, week 20.

The primary endpoint is change in lesion volume assessed by MRI, reported as a percentage of volume. The specified time points are baseline and week 20. This endpoint focuses on change in the size of the measured lesion rather than on a symptom score or a broader assessment of health. MRI is an imaging method, and lesion volume offers a quantitative way to describe an anatomic measurement over time.

For each group, the registry reports a mean change and a standard deviation. The mean describes the group’s average reported change; the standard deviation describes how dispersed individual measurements were around that average. The posted mean was 5.89 in the double-blind placebo group, with a standard deviation of 13.5. In the double-blind sildenafil group, the mean was -0.642 and the standard deviation was 18.3. In the open-label sildenafil group, the mean was -8.54 and the standard deviation was 12.1. The registry labels the unit as percentage of volume.

The endpoint description does not specify the sign convention used to calculate change. As a result, the direction of a positive or negative value should not be assigned a clinical interpretation beyond the recorded change measure without additional definition. The record also does not report a minimum change considered meaningful to participants or clinicians. MRI volume change is therefore the measure reported, not a complete account of every possible clinical outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant has a measured change in lesion volume, and the group results are summarized with a mean and standard deviation. A mean gives the arithmetic average of the included measurements. A standard deviation describes the spread of those measurements around their mean. It is not the same as a confidence interval and does not, by itself, express the precision of the estimated mean or of a difference between groups.

What can the group summaries tell us?

The reported means locate the average change in each analysis group, while the standard deviations show that individual values varied. For the double-blind placebo group, the reported mean was 5.89 and the standard deviation was 13.5. For double-blind sildenafil, the mean was -0.642 and the standard deviation was 18.3. For open-label sildenafil, the mean was -8.54 and the standard deviation was 12.1. The group counts were 7, 10, and 6, respectively. These summaries do not show the distribution of participant-level values, the presence of outliers, or the number of participants with any particular type of change.

In general, the mean can be sensitive to extreme observations, and the standard deviation can be influenced by them as well. With limited numbers of observations, the group summaries may not capture the full range of possible results. This is a general statistical consideration, not evidence that any particular value in this study was an outlier. Individual-level data and distributional details are not reported in the registry record.

Why does a comparison need more than two means?

A randomized comparison is ordinarily expressed as an estimated contrast between groups, alongside a measure of uncertainty. A confidence interval is a range of values compatible with the data and the statistical method used; it helps communicate the precision of an estimate. A p-value, when used, evaluates the data against a specified null hypothesis under stated assumptions. Neither a confidence interval nor a p-value can be recovered from the arm means and standard deviations alone without making analytical choices and assumptions.

The registry does not post a two-arm comparison for this continuous endpoint and lists no analysis entries. It states that values were missing or not estimable for a two-arm comparison. Thus, the posted group summaries do not provide an inferential estimate for sildenafil versus placebo. No confidence interval, p-value, adjustment method, or model result for that contrast is reported. The reason a comparison could not be posted is not reported in the registry record.

How should variability be considered?

In general, over-dispersion means that observed variation is greater than a model assumes. If a statistical model assumes less variation than is actually present, its uncertainty estimates may be too narrow. Conversely, a model that accounts for the relevant variation can better reflect uncertainty. The registry supplies standard deviations for the endpoint groups but does not report a model, a distributional assessment, or an over-dispersion analysis. It is therefore not possible to say whether over-dispersion was assessed or whether a particular model would be appropriate from the posted record alone.

The standard deviation describes participant-to-participant spread; it is not a test of a treatment effect. A large spread can make a group mean less informative about the experience of any one participant. Interpreting a mean as a reliable estimate of a broader population also depends on the study design, the analysis population, and assumptions about how participants entered and left the analysis. Those details are not fully described in the posted results.

What do planning illustrations represent?

In general, sample-size planning estimates ask how many participants per arm would be needed for a chosen statistical objective under specified assumptions. The planning assumptions described for this study use a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. Such estimates are illustrations based on those assumptions. They are not observed power, do not show what power the completed trial achieved, and do not establish the sample size chosen by the study team. The registry record does not report the original sample-size justification or the assumptions used to set the trial’s enrollment target.

The observed group sizes and the planning illustrations answer different questions. The group counts describe participants contributing to the posted endpoint summaries. A planning illustration describes a hypothetical design under its stated assumptions. Neither should be substituted for an analysis of the treatment contrast. No recalculated two-arm comparison is reported because the record identifies the continuous comparison as missing or not estimable; the sponsor’s own analysis takes precedence if a discrepancy is identified, and no discrepancy is recorded.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Double-Blind Placebo", "Open-Label Sildenafil", "Double-blind Sildenafil")
n   <- c(7, 6, 10)
m   <- c(5.89, -8.54, -0.642)
sp  <- c(13.5, 12.1, 18.3)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Double-Blind Placebo  7  5.890  13.500  -6.595  18.375
CARM  Open-Label Sildenafil  6  -8.540  12.100  -21.238  4.158
CARM  Double-blind Sildenafil  10  -0.642  18.300  -13.733  12.449

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one secondary outcome: change in the subject’s assessment of change in lymphatic malformation overall score. Its result is not included in the posted primary endpoint summaries. Although the record identifies a primary endpoint and a secondary outcome, it does not report a testing hierarchy, a multiplicity adjustment, or a plan for interpreting results across outcomes. It is therefore not possible to determine how the study addressed the chance of false-positive findings across multiple statistical tests, if such tests were performed.

The registry record lists no analysis entries and does not provide an inferential comparison for the primary continuous endpoint. A protocol-level statistical plan, analysis timing, interim analyses, or prespecified subgroup analyses are not reported in the registry record. Their absence from the posted record does not establish whether they were considered elsewhere.

The primary endpoint population is described as participants who completed each treatment period. This is a completion-based analysis population, not necessarily all participants randomized. The group summaries include 7 participants in the double-blind placebo group, 10 in the double-blind sildenafil group, and 6 in the open-label sildenafil group. The record does not explain exclusions, missing MRI measurements, withdrawal reasons, or the handling of incomplete measurements.

Methods such as imputation or sensitivity analyses can be used in general to examine the effect of missing outcome data, but no such method is reported. The registry also does not state whether an intention-to-treat analysis was performed. Without those details, the influence of missing observations on the posted summaries cannot be assessed.

12. 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 serious adverse event counts separately for the three safety groups. There were 0 serious adverse events among 8 participants at risk in the double-blind placebo group, 0 among 6 at risk in the open-label sildenafil group, and 0 among 10 at risk in the double-blind sildenafil group. The record reports 0 deaths in each group.

These are observed counts within the listed safety populations. A count of zero means no serious adverse events were recorded for that group in the registry results; it does not show that the underlying risk is zero. With finite group sizes, an event that was not observed may still be possible. The registry does not report a comparative safety estimate or an uncertainty interval for these counts.

The record also reports other adverse events affecting 8 of 8 participants in the placebo group, 5 of 6 in the open-label sildenafil group, and 10 of 10 in the double-blind sildenafil group. These counts are separate from the serious adverse event counts. The registry does not provide the terms for the serious events, and no top serious-event terms are listed. Adverse-event counts alone do not establish a causal relationship with study treatment.

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

The results describe MRI-measured lesion-volume change among participants included in each treatment-period analysis. The mean was 5.89 in the double-blind placebo group, -0.642 in the double-blind sildenafil group, and -8.54 in the open-label sildenafil group. The accompanying standard deviations—13.5, 18.3, and 12.1, respectively—show that the participant measurements varied within groups. These summaries are a record of the observed measurements, not a complete estimate of the comparative treatment effect.

The posted results do not establish whether the blinded sildenafil and placebo groups differed in a statistically reliable way. No two-arm comparison, confidence interval, or p-value is reported for the primary continuous outcome. The open-label group has a separate treatment context and should not be read as a randomized blinded comparison. Also, because the sign convention for change is not described, the positive and negative values should not be translated into a direction of clinical benefit or harm on the basis of the record alone.

The endpoint is an MRI volume measure. It does not, by itself, describe symptoms, function, quality of life, or every other outcome relevant to participants. A secondary subject-assessment outcome is listed, but its result is not present in the posted data. The record therefore does not support conclusions about that outcome.

The trial’s results also do not establish how representative the analysis groups are of all children with lymphatic malformations. The record reports completion-based endpoint populations but does not provide enough information about missing measurements, exclusions, or participant-level results to assess their influence. The posted safety counts similarly describe observed events in the listed groups, without comparative estimates or evidence that an event was caused by treatment.

These limits do not make the descriptive summaries uninformative. They define what the summaries can support: a description of the reported group means, variability, analysis counts, and safety counts. Stronger claims about comparative effects, precision, or clinical meaning require analyses and definitions that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why a randomized design and a posted treatment comparison are not the same thing. Random allocation is listed, and the registry reports placebo and double-blind sildenafil groups. Yet the posted primary outcome results consist of separate group means and standard deviations, with no two-arm contrast or uncertainty interval. Readers need the contrast and its precision to judge what the randomized comparison says; group summaries alone do not supply that inferential result.

The record also distinguishes blinded treatment from an open-label extension. Keeping those settings separate is important statistically because the summaries answer different descriptive questions. A mean in the open-label group does not replace the blinded placebo-controlled comparison. The registry reports values for each group, but it does not provide a randomized contrast involving the open-label group.

The endpoint and analysis population matter as well. MRI lesion-volume change is a quantitative outcome, while the primary analysis includes participants who completed each treatment period. These choices define what is being summarized. The record does not report enough information about missing measurements or participant flow to establish how the completion-based summaries relate to all randomized participants.

Finally, the study demonstrates the distinction between descriptive results, inferential analysis, and sample-size planning. Means and standard deviations describe the posted observations. A treatment comparison would quantify an estimated difference and uncertainty. Planning illustrations based on the observed effect are hypothetical design calculations, not observed power and not evidence about the original sample-size rationale. Keeping these roles distinct helps prevent an observed group pattern from being mistaken for a confirmed treatment effect.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation of the posted efficacy results is the absence of an estimable two-arm comparison for the continuous primary endpoint. Although group means and standard deviations are reported, the record supplies no contrast, confidence interval, or p-value. The reason the comparison was missing or not estimable is not reported. No statistical analysis entries are listed.

The endpoint summaries are based on participants who completed each treatment period. The registry does not report the number randomized to each group in the posted endpoint results, why participants were not included in the analysis, how many MRI measurements were missing, or how missing data were handled. This limits assessment of how well the reported summaries represent the randomized groups.

The record provides little detail for interpreting the MRI measure. It identifies lesion-volume change, baseline and week 20, and percentage of volume, but does not specify the sign convention or a threshold for clinically meaningful change. Nor does it provide participant-level values or distributions. The large within-group standard deviations indicate variability, but do not reveal its source or shape.

The study’s timing descriptions include a 32-week duration in the brief summary and an expected average of 20 weeks in the primary endpoint description, with the endpoint measured at week 20. The record does not explain how these durations relate to each other. It also does not detail the open-label extension sequence, masking procedures, or the distinction between the registry’s quadruple-masking classification and the brief description’s double-blind assignment.

Finally, the registry does not report a statistical plan, multiplicity handling, interim analyses, or sample-size justification. A secondary outcome is named but its result is not available in the posted results. These omissions restrict interpretation to the descriptive primary endpoint and safety information recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Sildenafil for the Treatment of Lymphatic Malformations — NCT02335242.
• Registry record last updated 2022-11-17; status last verified 2022-10.
• Results first posted 2022-11-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes a completed randomized Phase 2 parallel-group study of oral sildenafil for lymphatic malformations, sponsored by Stanford University. It lists enrollment of 22, quadruple masking, placebo and sildenafil interventions, and an open-label sildenafil extension for placebo recipients. The primary outcome is MRI-measured lesion-volume change from baseline to week 20.

For the primary endpoint, the posted means and standard deviations are 5.89 and 13.5 for double-blind placebo, -0.642 and 18.3 for double-blind sildenafil, and -8.54 and 12.1 for open-label sildenafil. The analysis includes participants who completed each treatment period. No two-arm comparison or registry analysis entry is posted. Serious adverse event counts and deaths are 0 in each safety group; other adverse events are reported separately.

The record does not report a statistical plan, sample-size justification, missing-data method, or the reason the primary comparison was not estimable. Interpretation is therefore limited to the posted group summaries and event counts.