This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation (NCT02428296), a na phase 2 study. The primary outcome is Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02428296 |
| Phase | Phase 2 |
| Condition | PIK3CA-Related Overgrowth Spectrum (PROS), Growth Disorder, Genetics |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 39 |
| Arms in the primary outcome | n/a |
| Lead sponsor | National Human Genome Research Institute (NHGRI) |
| Results posted | Yes |
2. Clinical Question
Population
People ages 3 to 65 years old with a confirmed somatic mutation or alteration of the PIK3CA gene in affected tissue and a diagnosis within PIK3CA-related overgrowth spectrum (PROS). The primary endpoint description says that the anatomy of 23 patients permitted analysis of affected versus unaffected tissue by DXA.
Intervention
Sirolimus, taken once or twice a day during the treatment period. The registry describes a phase 2, single-group, open-label study.
Comparator
The planned comparison is within the study: tissue-volume change during the treatment period is considered alongside change during the run-in period. Affected tissue is also measured against unaffected tissue where anatomy permits. There is no randomized control group.
Primary question
How does the mean percentage change in affected and unaffected fibrofatty tissue volume, measured by DXA, differ between the run-in period and the period when participants take sirolimus? The registry record does not report numerical results for this endpoint.
PROS is described in the registry as a condition caused by changes in the PIK3CA gene that can lead to overgrowth in fatty, vascular, and other tissues. The study asks whether tissue overgrowth changes over time and whether it reduces or stabilizes during sirolimus treatment. Its focus is change in measured tissue volume, rather than a randomized comparison of treatment with a concurrent control.
The intended sequence was monitoring during the first 6 months, followed by sirolimus during the next 6 months. The primary endpoint description identifies the run-in as weeks 0-26 and treatment as weeks 26-52. These repeated measurements allow the investigators to compare change across periods within the study, but do not by themselves separate a treatment effect from other influences on change over time.
3. Trial Design
This is a phase 2, nonrandomized, open-label, single-group pilot study sponsored by the National Human Genome Research Institute. The registry lists enrollment of 39 and the study status as completed. The recorded study start is 2015-04-23, and primary completion is listed as 2018-02-14. Allocation is listed as not applicable, and masking as none.
Participants had to be ages 3 to 65 years old and have a confirmed PIK3CA mutation or alteration in affected tissue. The planned study sequence included a run-in period to monitor overgrowth, followed by a treatment period with sirolimus. The brief description says participants would take sirolimus once or twice daily. Clinic assessments were to include blood and urine tests, photographs, and imaging such as MRI and DXA, with possible x-rays and CT scans. The registry also describes clinic visits and a month-long visit, but does not provide further detail about how these visits relate to the analysis schedule.
The primary endpoint is based on DXA measurements of affected and unaffected tissue. The record states that anatomy permitted this comparison for 23 patients. That endpoint population is therefore described separately from the overall enrollment; the registry record does not explain why DXA analysis was not possible for the others, or how missing measurements were handled.
Because the study has no randomized comparator and participants and investigators were not masked, its design is descriptive and exploratory. Changes during the run-in offer a within-study reference period, not a concurrent untreated control. The registry record does not report a detailed statistical analysis plan, the rationale for the enrollment target, or whether interim analyses were planned.
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
| Stage | PIK3CA-Related Overgrowth Spectrum Patients |
|---|---|
| STARTED | 39 |
| Treated | 39 |
| COMPLETED | 30 |
| NOT COMPLETED | 9 |
Reasons for not completing this period:
| Reason | PIK3CA-Related Overgrowth Spectrum Patients |
|---|---|
| Adverse Event | 7 |
| Withdrawal by Subject | 2 |
Analysis population for the primary outcome, as defined in the registry: The anatomy of 23 patients permitted DXA analysis of affected versus unaffected tissue.
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.
| Characteristic | Unit | PIK3CA-Related Overgrowth Spectrum Patients |
|---|---|---|
| Participants analysed | 39 | |
| Age, Continuous | years | 16.6 (3 to 48) |
| Age, Customized: Age – 3-16 years | Participants | 23 |
| Age, Customized: Age – 17-48 years | Participants | 16 |
| Sex: Female, Male: Female | Participants | 17 |
| Sex: Female, Male: Male | Participants | 22 |
| Race and Ethnicity Not Collected | Participants | — |
| Region of Enrollment: United States | Participants | 13 |
| Region of Enrollment: France | Participants | 15 |
| Region of Enrollment: United Kingdom | Participants | 11 |
6. Primary Endpoint
The registry lists the primary outcome as Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA, measured over Run-in (0-26 weeks), treatment (26-52 weeks).
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | mean percentage change in tissue volume |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the mean percentage change in affected and unaffected fibrofatty tissue volume measured by DXA. The registry describes measurements at week 0, week 26, and week 52. The run-in change covers weeks 0-26, while the treatment-period change covers weeks 26-52. The endpoint description says absolute volumes at those time points were used to characterize change across periods. The anatomy of 23 patients permitted analysis of affected versus unaffected tissue.
DXA provides a quantitative way to assess tissue composition and volume. Repeated measurement can describe whether the measured tissue changes over time, and comparing affected with unaffected tissue can provide context about the pattern of change within a participant. The unaffected tissue measurement is not a randomized control: it may differ biologically or anatomically from the affected site, and the registry record does not report how such differences were accounted for.
The endpoint is useful for making a structural measurement rather than relying only on a general impression of overgrowth. However, its interpretation depends on measurement quality, the availability of usable scans, and the analysis definition. Although the registry describes the intended outcome and calculation, it does not report the observed mean changes, their variability, or an estimate of the difference between periods. Thus, the endpoint’s numerical result and precision cannot be assessed from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes a study designed to measure tissue-volume change before and during sirolimus treatment, but it does not report numerical primary-outcome results. It gives no observed mean percentage change, standard deviation, confidence interval, or test result for the primary endpoint. The registry also lists no reported analyses. Consequently, the direction, magnitude, and precision of the primary outcome cannot be evaluated from this record.
The design matters for interpreting any within-study change. Participants were monitored during a run-in period and then received sirolimus, so the periods occur in sequence rather than being compared concurrently through random allocation. A difference in observed change between the periods could reflect treatment, but it could also reflect natural variation over time, changes in measurement, or other influences. The registry record does not report an analysis that would distinguish among these explanations.
The affected-versus-unaffected tissue comparison adds a reference measurement, but it is not equivalent to a randomized control group. The tissues may differ in location or characteristics, and the record does not describe adjustment for those differences. Nor does it report whether the affected and unaffected measurements were analyzed as paired observations, how multiple tissue types were handled, or how the analysis addressed participants whose anatomy did not permit DXA comparison.
For a continuous endpoint, a mean describes the average observed change, while a standard deviation describes variation among observations. A confidence interval, if reported, would show the range of values compatible with the analysis under its assumptions and would communicate precision. None of these numerical summaries for the primary endpoint appears in the registry record, so no claim about the size or uncertainty of change is supportable from the posted results.
The safety record reports adverse-event counts for the study group, including serious adverse events for 12 of 39 participants, other adverse events for 31 of 39, and 0 deaths. These figures describe events recorded during the study; they do not by themselves establish whether an event was caused by sirolimus. The registry lists several serious-event terms at 2.6% each, but does not provide enough information to interpret comparative risk because there is no control group.
Overall, the available registry information establishes the study’s question, design, endpoint definition, and selected safety summaries. It does not establish the magnitude or precision of the primary endpoint result. The absence of a reported primary result is a limitation of the registry record, not evidence that tissue volume did or did not change.
9. Statistical Methods Explained
The endpoint is a continuous measurement expressed as mean percentage change in tissue volume. The registry describes DXA measurements for affected and unaffected tissue at week 0, week 26, and week 52. It designates weeks 0-26 as the run-in period and weeks 26-52 as the treatment period. This setup produces a sequence of measurements over time rather than a randomized comparison between treatment groups.
What does a mean describe?
In general, a mean is an average across the observations included in an analysis. It can describe the typical direction and size of measured change, but it does not show how similar or different the individual observations are. A mean can also be influenced by unusually large or small values. For that reason, interpretation usually considers the mean alongside a measure of variability, such as the standard deviation. The registry identifies standard deviation as the dispersion measure for the primary outcome, but does not report a numerical mean or standard deviation.
What does the within-study comparison show?
In general, comparing change across periods within the same study can describe how the observed pattern differs over time. Because the run-in precedes treatment, the periods are not exchangeable by design: time and treatment status change together. A difference across periods therefore cannot, on its own, be attributed to treatment. Random allocation to a concurrent control group can help balance other influences on average; this study is listed as nonrandomized and single-group, so that protection is not present.
The endpoint also describes affected and unaffected tissue. In general, measuring both can offer an internal reference for the pattern of tissue change. It does not make unaffected tissue a randomized control, and the record does not state whether the statistical analysis used paired differences or another model. The record also does not specify whether analyses were adjusted for baseline volume, age, tissue site, or other characteristics.
Why does the standard deviation matter?
In general, the standard deviation describes how dispersed observations are around their mean. A relatively broad spread means that participants’ measured changes vary more, so a mean alone may be less representative of individual observations. If observations are more variable than a statistical model assumes, uncertainty estimates and tests based on that model can be unreliable. Over-dispersion is a general concern when observed variability exceeds what a model allows; the registry record does not report whether it was assessed or whether any model was used to address it.
What would a confidence interval add?
In general, a confidence interval communicates the precision of an estimate by giving a range of values compatible with the data and the method’s assumptions. A narrow interval indicates greater precision than a wide interval, although precision is not the same as freedom from bias. The registry record does not report a confidence interval for the primary endpoint, so neither the estimated range nor its precision can be assessed.
How should a significance test be read?
In general, a significance test evaluates how compatible the observed data are with a specified null model. A p-value does not measure the probability that the treatment works, nor does it establish that an observed difference is clinically important. Interpretation also depends on the analysis plan, assumptions, and whether multiple outcomes or comparisons were examined. The registry record does not report a primary endpoint p-value or a detailed testing plan.
What is the role of sample-size planning?
In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, variability, significance level, power, and design. It is not an observed result and does not establish the probability that a completed study detected an effect. The registry record does not report the study’s own sample-size justification. It describes planning illustrations based on an observed effect and specified assumptions, but no numerical illustration results are reported in the record. Such illustrations should not be interpreted as observed power.
For this study, the central methodological limitation is not a calculation that can be corrected from the record; it is the lack of reported primary-outcome estimates and analysis details. The record does not describe the precise model, handling of repeated measurements, missing-data method, or adjustments. Without those details and the numerical results, the endpoint definition can be explained, but the primary finding cannot be independently evaluated.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists five outcome measures and identifies the DXA tissue-volume measure as the primary outcome. It also lists secondary outcomes concerning mean sirolimus doses to achieve the target plasma concentration, quality of life, and hospitalizations and surgical interventions. The record does not report a multiplicity strategy, such as whether testing across outcomes was adjusted or which outcomes were intended to be confirmatory. In general, examining multiple outcomes can increase the chance of at least one apparently unusual result, so the prespecified hierarchy and interpretation plan matter.
Missing-data handling is not reported in the registry record. The primary endpoint description says that the anatomy of 23 patients permitted DXA analysis, while enrollment was 39. The record does not explain why other participants were not included in that endpoint population, whether measurements were unavailable at particular time points, or how missing measurements were treated. It also does not report sensitivity analyses to assess the effect of missing data.
The analysis population is not described in detail beyond the stated endpoint population. The record does not say whether the primary analysis included all enrolled participants who began treatment, only those with usable DXA measurements, or another defined group. Nor does it report how treatment discontinuation or incomplete follow-up was handled.
These omissions limit interpretation of both the endpoint estimate and its precision. In general, analyses based on participants with complete measurements can be affected if measurement availability is related to health status or observed change. The registry record does not provide enough information to determine whether that issue arose or how it was addressed.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| PIK3CA-Related Overgrowth Spectrum Patients | 12 | 39 | 30.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| PIK3CA-Related Overgrowth Spectrum Patients | 0 of 39 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| PIK3CA-Related Overgrowth Spectrum Patients | 31 of 39 |
Most frequent serious adverse event terms
| Event term | Organ system | PIK3CA-Related Overgrowth Spectrum Patients |
|---|---|---|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | 1 of 39 |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | 1 of 39 |
| Neutropenia | Blood and lymphatic system disorders | 1 of 39 |
| Anemia | Blood and lymphatic system disorders | 1 of 39 |
| Neutropenic fever | Blood and lymphatic system disorders | 1 of 39 |
| Constipation aggravated | Gastrointestinal disorders | 1 of 39 |
| Appendicitis | Infections and infestations | 1 of 39 |
| Cellulitis | Infections and infestations | 1 of 39 |
| Epstein Barr Virus | Infections and infestations | 1 of 39 |
| Pelvic infection | Infections and infestations | 1 of 39 |
Most frequent non-serious adverse event terms
| Event term | Organ system | PIK3CA-Related Overgrowth Spectrum Patients |
|---|---|---|
| Infections and infestations | Infections and infestations | 16 of 39 |
| Blood and lymphatic disorders | Blood and lymphatic system disorders | 8 of 39 |
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | 3 of 39 |
| Vascular disorders | Vascular disorders | 3 of 39 |
| Gastrointestinal disorders | Gastrointestinal disorders | 2 of 39 |
| Nervous system disorders | Nervous system disorders | 2 of 39 |
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | 2 of 39 |
| Skin and subcutaneous disorders | Skin and subcutaneous tissue disorders | 2 of 39 |
| Injury, poisoning, and procedural complications | Injury, poisoning and procedural complications | 1 of 39 |
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | 1 of 39 |
Serious events with the highest arm-level rate: pneumonia (2.6%), pneumonitis (2.6%), neutropenia (2.6%), anemia (2.6%), neutropenic fever (2.6%).
The registry reports safety information for the PIK3CA-related overgrowth spectrum study group. Serious adverse events were reported for 12 of 39 participants, and other adverse events were reported for 31 of 39. The record reports 0 deaths. The listed serious-event terms include pneumonia, pneumonitis, neutropenia, anemia, neutropenic fever, and constipation aggravated; each is reported at 2.6%.
These figures are descriptive counts and percentages from a single-group study. They do not compare sirolimus with an untreated or alternative-treatment group, and they do not by themselves show whether an event was caused by the study drug. The registry record does not report event timing, duration, severity beyond the serious-event classification, or a detailed attribution assessment. It also does not provide exposure-adjusted rates or a breakdown by treatment duration.
Adverse-event categories may include more than one event per participant, and the record does not describe the overlap between the serious and other adverse-event summaries. The listed percentages should therefore be read as reported, not used to infer additional counts or totals. The reported 0 deaths is a registry safety observation for this study; it does not establish the absence of other risks.
12. What the Result Does, and Does Not, Mean
This record establishes that a phase 2, nonrandomized, open-label pilot study was conducted to examine sirolimus therapy for segmental overgrowth associated with somatic PIK3CA activation. It describes a planned period of monitoring followed by treatment and defines a primary endpoint based on DXA measurement of affected and unaffected fibrofatty tissue. The registry lists enrollment of 39 and says that the anatomy of 23 patients permitted the DXA analysis.
The record does not report numerical primary-outcome results. It therefore cannot show from the posted results whether mean tissue volume increased, decreased, or remained stable during either period, or how precisely any change was estimated. The missing result should not be interpreted as a finding of no change. It means that the primary endpoint’s numerical estimate is not reported in the registry record.
Even if a within-study change estimate were available, the design would require cautious causal interpretation. Participants were not randomized to sirolimus or a concurrent control, and the treatment period followed the run-in. A difference between periods could reflect treatment or other time-related influences. The affected-versus-unaffected tissue measurement is informative as a within-study reference but is not a randomized comparison.
The safety summaries describe events recorded in the study group, including serious adverse events, other adverse events, and deaths. Without a comparison group and further event details, these summaries cannot establish comparative risk or attribution to sirolimus.
In general, a pilot study can characterize feasibility, measurement procedures, and patterns that may inform later research. The registry record does not report a statistical plan or enough outcome information to evaluate the strength of evidence for the primary question. The appropriate conclusion is limited: the study was designed to assess tissue-volume change and recorded safety events, while the numerical primary result and its uncertainty are not reported.
13. Why This Trial Matters Statistically
This study raises a useful statistical problem: how to measure change in a condition that can affect different tissues and body sites, and how to interpret repeated measurements when treatment follows an observation period. DXA gives the endpoint a quantitative basis, while measuring affected and unaffected tissue offers additional context. The record’s note that anatomy permitted this comparison for 23 patients also makes clear that the endpoint population may differ from overall enrollment.
The single-group sequence is important because it illustrates the distinction between observed change and a treatment effect. Repeated measurements can describe what happened across time periods, but they cannot by themselves rule out changes that would have occurred without treatment. A run-in period provides useful context, yet it is not a concurrent randomized control. This distinction is central when reading results from nonrandomized studies.
The study also highlights why estimates need accompanying uncertainty and transparent analysis details. A mean change without a measure of variability or confidence interval gives limited information about how consistently participants changed and how precisely the average is known. The registry record does not report those primary-outcome summaries or the analysis plan, so the methodological question is visible even though the result cannot be assessed.
Finally, the difference between enrollment and the stated DXA-analysis population makes missing-data and analysis-population definitions relevant. The registry does not explain the difference or describe its handling. Clear reporting of who contributed to each endpoint, why measurements were unavailable, and how uncertainty was estimated would help readers judge the scope and reliability of the findings.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The primary limitation for interpreting efficacy is that numerical results for the primary endpoint are not reported in the registry record. The mean change, standard deviation, confidence interval, and test result are absent, so the size and precision of the observed tissue-volume change cannot be assessed.
The study is nonrandomized, open-label, and single-group. Its run-in and treatment periods occur in sequence, leaving treatment status entangled with time. The registry record does not report a concurrent control group, and the unaffected tissue measurement is not a randomized comparator. These design features limit causal interpretation of any change.
The record says that the anatomy of 23 patients permitted DXA analysis, while enrollment was 39. It does not explain the difference, report the availability of measurements at each time point, define the primary analysis population, or describe missing-data methods. This makes it difficult to understand which observations would contribute to the endpoint and whether the analysis could be affected by incomplete measurement.
Further details are also not reported in the registry record: a full statistical analysis plan, the model for repeated measurements, handling of multiple outcomes, any adjustment for relevant characteristics, and a sample-size justification. Safety reporting is limited to selected counts, percentages, and serious-event terms; details about timing and attribution are not given. These limitations concern what can be learned from the registry record and do not establish that the underlying study analyses were not conducted.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation — NCT02428296.
- Registry record last updated 2020-02-05; status last verified 2018-02-14.
- Results first posted 2020-01-27.
- 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.
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18. Record Summary
NCT02428296 is a completed phase 2, nonrandomized, open-label, single-group pilot study of sirolimus for segmental overgrowth associated with somatic PIK3CA activation. The registry lists enrollment of 39 and identifies the National Human Genome Research Institute as sponsor.
The primary endpoint is mean percentage change in affected and unaffected fibrofatty tissue volume measured by DXA across the run-in period, weeks 0-26, and the treatment period, weeks 26-52. The registry says that the anatomy of 23 patients permitted the DXA comparison. Numerical primary-outcome results and detailed analysis methods are not reported in the registry record.
Safety information includes serious adverse events for 12 of 39 participants, other adverse events for 31 of 39, and 0 deaths. The record does not establish event attribution or comparative risk.