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 Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes (NCT00971789), a na phase 2 study. The primary outcome is Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00971789 |
| Phase | Phase 2 |
| Condition | Cowden's Disease, Hamartoma Syndrome, Multiple |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 18 |
| Arms in the primary outcome | n/a |
| Lead sponsor | National Cancer Institute (NCI) |
| Results posted | Yes |
2. Clinical Question
Population
Adults with Cowden syndrome or another PTEN hamartomatous tumor syndrome were eligible. The registry describes these syndromes as involving germline PTEN mutations and notes that hamartomas can occur throughout the body. Enrollment was 18. The record does not report how many participants had cancer, how many had each syndrome, or other baseline clinical characteristics.
Intervention
Participants received sirolimus. The arm description gives a 6 mg oral loading dose followed by 2 mg orally each day in a 28-day treatment cycle. Participants without cancer were to take the drug for two cycles, or 56 days, unless unacceptable side effects developed. Participants with cancer could continue beyond cycle 2 until disease worsened or unacceptable side effects developed.
Comparator
There was no concurrent comparison group. The registry identifies a single-group model, with allocation listed as NA and masking listed as none. This design can describe outcomes among treated participants, but it does not provide a randomized control group for separating treatment-related changes from other explanations.
Primary question
The primary objective was to assess biochemical changes in benign and malignant tumor tissue, using immunohistochemistry to evaluate protein levels associated with cell growth. The planned assessment points were baseline, day 14, and day 56. However, no participant underwent biopsy after study treatment, so no post-treatment tissue analysis was done. The primary question therefore has no reported outcome result in the registry record.
3. Trial Design
This was a completed phase 2 pilot study with a single-group design. It enrolled 18 people with Cowden syndrome or other syndromes characterized by germline PTEN mutations. The registry record lists the study start as 2008-07 and primary completion as 2012-10. The National Cancer Institute was the sponsor. No random allocation or masking was used; allocation is listed as NA and masking as none.
Participants received sirolimus. The arm description specifies an oral loading dose of 6 mg and an oral daily dose of 2 mg during a 28-day treatment cycle. The study summary says participants without cancer were to receive two cycles, totaling 56 days, unless unacceptable side effects developed. Participants with cancer could continue treatment beyond cycle 2 until disease worsened or unacceptable side effects developed. The record does not report how many participants followed each treatment duration or their actual exposure.
The primary outcome concerned changes in protein levels in benign and malignant tumor tissue, with planned measurements at baseline, day 14, and day 56. The record states that no participant underwent biopsy after study treatment, preventing the planned post-treatment tissue analysis. It lists two outcome measures overall, but no statistical analyses are reported. The registry record does not report a statistical analysis plan, a protocol justification for enrollment, interim analyses, or details of analysis populations. These omissions mean that the treatment schedule and planned outcome can be described, but the intended analysis procedures cannot be reconstructed from the record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Sirolimus Patients |
|---|---|
| STARTED | 18 |
| COMPLETED | 18 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: No patient underwent biopsy after the study treatment, so no such tissue analysis was done.
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 | Sirolimus Patients |
|---|---|---|
| Participants analysed | 18 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 15 |
| Age, Categorical: >=65 years | Participants | 3 |
| Age, Continuous | years | 43.54 (SD 15.54) |
| Sex: Female, Male: Female | Participants | 9 |
| Sex: Female, Male: Male | Participants | 9 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 18 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 17 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 18 |
6. Primary Endpoint
The registry lists the primary outcome as Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry., measured over Baseline, day 14, and day 56.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was a biochemical change in benign or malignant tumor tissue assessed by immunohistochemistry. The stated definition focused on decreases in protein levels, including P-AKT, total S6, P-S6, and P-4E-BP1. The description links these proteins to cell growth and specifies tissue staining as the measurement approach.
The scoring plan combined staining distribution and staining intensity. Distribution represented the percentage of positive cells in a tissue core, with scores of 0 for 0%, 1 for 1% to 50%, and 2 for 51% to 100%. Intensity was scored from 1 for weak staining to 3 for strong staining. The distribution and intensity scores were to be summed into a total score. The planned measurement times were baseline, day 14, and day 56.
In general, a tissue biomarker endpoint can provide a biological measure of pathway activity in sampled tissue. It is not by itself a measure of how a participant feels, functions, or experiences a clinical outcome. Interpretation also depends on obtaining comparable samples and applying a consistent scoring procedure. In this study, the registry explicitly states that no participant underwent biopsy after treatment, so no post-treatment tissue analysis was done. Consequently, the intended within-participant biochemical change cannot be estimated from the posted results. The record does not report baseline tissue scores or a numerical endpoint result.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive point is that the primary outcome has no result in the registry record. Although the study planned to compare immunohistochemical protein scores at baseline, day 14, and day 56, no participant underwent biopsy after treatment. Without post-treatment tissue samples, the planned biochemical change could not be assessed. The registry therefore does not establish whether the measured proteins increased, decreased, or remained unchanged during treatment.
The study’s single-group design also limits what could be concluded even if outcome measurements had been available. A change observed over time in a treated group would not, on its own, show that treatment caused the change. Natural fluctuation, changes in sampled tissue, measurement variability, and other events during follow-up can also contribute to within-group patterns. A concurrent comparison group can help evaluate such alternatives; this study had none.
The endpoint was a tissue-based biological measure, not a clinical outcome. A biomarker result, if available, would describe the measured tissue staining under the stated scoring approach. It would not by itself establish a change in symptoms, cancer risk, tumor progression, or any other clinical outcome. The registry record does not report results for those questions.
The adverse-event record lists 0 serious adverse events among 18 participants at risk and 17 participants with other adverse events among 18 at risk. These figures describe recorded event categories. They do not establish that sirolimus caused the events, and the registry record does not provide event-level descriptions in the posted results. Deaths are not reported in the record. The absence of a reported serious event count is not a substitute for a complete account of event types, timing, or attribution.
No statistical analyses are reported, and the record gives no p-values, confidence intervals, or estimates of the primary endpoint. The enrollment count alone cannot show how precisely an outcome was estimated, particularly when the outcome was not measured after treatment. Any planning calculations should be read as illustrations under their stated assumptions, not as evidence that the study observed a treatment effect or had a particular probability of detecting one.
9. Statistical Methods Explained
The registry describes a phase 2 pilot study with one treatment group. This design can document what happened among participants receiving the study drug, but it does not make a randomized comparison. With no control group, differences over time cannot be attributed to treatment with the same strength as a controlled comparison. This is a general design limitation, not a statement that any particular unmeasured factor affected this study.
What does a single-group design show?
In general, a single-group study can describe feasibility, treatment exposure, recorded adverse events, and changes that are measured within participants. For a before-and-after outcome, each participant’s later measurement can be interpreted in relation to that participant’s baseline, if both measurements exist. However, a before-and-after pattern has no concurrent untreated or alternative-treatment group to indicate what might have happened over the same period without the study treatment. The registry does not report a comparison group, and its allocation entry is NA.
Masking was listed as none. In general, masking can reduce the possibility that expectations influence care, assessment, or interpretation. The extent to which lack of masking matters depends on the outcome and assessment process. The planned primary endpoint relied on tissue staining and scoring; the registry does not report whether assessors were blinded to sample timing or other sample information.
How was the primary endpoint intended to be measured?
The planned endpoint used immunohistochemistry to assess selected protein levels in tumor tissue. The stated scoring approach combined staining distribution and intensity into a total score. This creates an ordered score based on categories rather than a direct continuous measurement of protein concentration. In general, ordered scoring can make visual assessments more structured, but category boundaries and interpretation can affect the resulting score. The registry describes the scoring categories but does not report assessor training, reproducibility checks, or a statistical method for analyzing the total score.
The planned time points were baseline, day 14, and day 56. Repeated measurements can, in general, show how an outcome changes over time within the same participant. Such analysis depends on having measurements at the relevant times and a prespecified approach for handling incomplete records. Here, the registry states that no participant underwent biopsy after study treatment, so the planned post-treatment tissue analysis was not performed. It does not report baseline scores or an analysis of change.
What do confidence intervals and p-values usually contribute?
In general, a confidence interval describes the range of values compatible with an estimate under the statistical model and its assumptions. A narrower interval indicates greater precision, while a wider interval indicates greater uncertainty. A p-value evaluates how unusual the observed data would be under a specified null model; it does not measure the probability that the null hypothesis is true, and it does not measure clinical importance. No confidence interval, p-value, or primary-outcome estimate is reported in this record, so these tools cannot be used to characterize the primary result.
Over-dispersion is a general concern when outcome variability is greater than a model assumes. If a model understates variability, uncertainty estimates can be too optimistic. The registry record does not identify a statistical model for the primary endpoint or report a distributional assessment, so there is no basis for saying whether over-dispersion was considered or relevant to an analysis performed.
How should the planning calculations be read?
The registry’s sample-size assumptions describe planning illustrations based on an observed effect, rather than the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a stated fraction of the observed effect. For time-to-event calculations, the stated quantity is total events; other calculations are expressed as participants per arm. These are planning assumptions, not observed power and not evidence of a treatment effect. The record does not report the trial’s own sample-size justification. Because the study was single-group, a hypothetical equal-allocation two-arm illustration should not be mistaken for the design actually used.
More broadly, a sample-size calculation depends on the effect size, variability, significance level, allocation, and analysis assumptions. If those assumptions differ from the eventual data or the intended design, the illustration may not describe the operating characteristics of the study. Since the primary tissue outcome was not analyzed, the registry record does not establish an observed endpoint effect on which to base conclusions about precision or statistical evidence.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures, but it does not report how multiple outcomes, proteins, tissue types, or time points were handled in statistical testing. The primary endpoint description names several proteins and multiple planned measurement times. Testing several outcomes can increase the chance of finding a nominally unusual result by chance when each is assessed separately. In general, an analysis plan may address this through a prespecified primary comparison, adjustment procedures, or a clearly exploratory interpretation. The registry record does not report such a plan, so it is not possible to determine whether multiplicity was addressed.
Missing data are especially consequential for the primary outcome. The record states that no participant underwent biopsy after study treatment, and therefore no post-treatment tissue analysis was done. This is not merely a small amount of incomplete endpoint follow-up: the planned post-treatment tissue endpoint has no reported measurements. The registry record does not report why biopsies were not performed, whether baseline specimens were available, or whether any alternative measurement was used. Those reasons and details should not be inferred.
The record does not report analysis populations, such as whether analyses were intended to include all enrolled participants, only participants who started treatment, or a subgroup with evaluable tissue. It also does not report a statistical analysis plan, rules for handling missing observations, or any inferential analysis. As a result, there is no basis for identifying a completed analysis population or evaluating whether exclusions could have affected an estimate. These gaps limit interpretation independently of the single-group design: even a descriptive estimate would require a defined outcome dataset and a transparent account of how missing observations were handled.
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 |
|---|---|---|---|
| Sirolimus Patients | 0 | 18 | 0.0% |
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 |
|---|---|
| Sirolimus Patients | 17 of 18 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Sirolimus Patients |
|---|---|---|
| ALT, SGPT (serum glutamic pyruvic transaminase) | Metabolism and nutrition disorders | 7 of 18 |
| Albumin, serum-low (hypoalbuminemia) | Metabolism and nutrition disorders | 7 of 18 |
| Fatigue (asthenia, lethargy, malaise) | General disorders | 7 of 18 |
| Hemoglobin | Metabolism and nutrition disorders | 7 of 18 |
| Diarrhea | Gastrointestinal disorders | 6 of 18 |
| Alkaline phosphatase | Metabolism and nutrition disorders | 5 of 18 |
| Cholesterol, serum-high (hypercholesteremia) | Metabolism and nutrition disorders | 5 of 18 |
| Triglyceride, serum-high (hypertriglyceridemia) | Metabolism and nutrition disorders | 5 of 18 |
| Constipation | Gastrointestinal disorders | 4 of 18 |
| Insomnia | General disorders | 4 of 18 |
The registry lists 0 serious adverse events among 18 participants at risk. It also lists 17 participants with other adverse events among 18 at risk. These are participant counts in the registry’s event categories, not counts of distinct event types or a measure of how many events each participant experienced. The record does not provide event-level descriptions in the posted safety summary.
The counts should not be interpreted as proving that treatment caused an event or that it was unrelated to treatment. The registry record does not report the event attribution, timing, duration, severity details for the other-event category, or the criteria used to classify events. Deaths are not reported in the registry record. A missing death value should not be read as a reported count of zero.
In general, safety counts describe what was recorded under the study’s reporting and classification procedures. They do not by themselves characterize the full clinical context, compare risk against another treatment, or resolve whether an event was treatment-related. The single-group design has no concurrent control group for a comparative safety estimate. The figures should therefore be read narrowly as the adverse-event counts posted for this treated group, with the limitations on detail and comparison kept in view.
12. What the Result Does, and Does Not, Mean
The record documents a completed phase 2 study of sirolimus in people with Cowden syndrome or other PTEN hamartomatous tumor syndromes. Its primary question concerned biochemical changes in benign and malignant tumor tissue, assessed by immunohistochemistry at baseline, day 14, and day 56. The registry explicitly states that no participant underwent biopsy after study treatment and that no such tissue analysis was done. Thus, the posted record does not provide a primary endpoint estimate or show the direction or size of any tissue-protein change.
This missing endpoint result does not mean that a measured value was unchanged. It means that the planned post-treatment tissue assessment was not available for analysis as reported. Nor can the endpoint be inferred from the treatment schedule, study completion status, or adverse-event counts. The record does not report an alternative primary outcome analysis that could answer the planned biochemical question.
The study’s single-group structure also means that it cannot offer a randomized comparison with an untreated group or another treatment. Even if a within-group change had been reported, a single-group pattern would not by itself distinguish a treatment effect from other time-related influences. The record does not report clinical outcome results that would establish effects on cancer, symptoms, or risk.
The posted safety counts describe serious and other adverse-event categories among participants at risk, but do not supply details sufficient to determine causation or comparative safety. The record also does not report a statistical analysis plan, endpoint estimates, confidence intervals, or p-values. Overall, the record describes the study’s purpose, design, treatment schedule, planned tissue endpoint, and some safety counts. It does not report an analyzed primary tissue result, and it cannot support a quantitative conclusion about the intended biochemical effect.
13. Why This Trial Matters Statistically
This study is statistically notable because its primary endpoint depended on obtaining tissue after treatment, while the registry states that no participant underwent a post-treatment biopsy. The design and endpoint description therefore do not lead to an analyzable primary comparison in the posted results. Recognizing this distinction is important: a clearly specified endpoint is not the same as an observed endpoint result.
The case also illustrates why design, measurement, and analysis need to be considered together. A single-group design can describe outcomes in treated participants, but it cannot provide a randomized counterfactual. A tissue biomarker can address a biological question, but it does not directly answer a clinical-outcome question. If planned tissue measurements are absent, neither the endpoint definition nor the treatment schedule can replace the missing observations.
Finally, the record distinguishes descriptive safety counts from inferential evidence. The listed adverse-event counts do not establish causation, and there is no concurrent group for estimating comparative safety. The sample-size assumptions are planning illustrations rather than observed power or evidence of efficacy. Taken together, these features make the study a useful example of how registry entries can document an intended scientific question while leaving the primary statistical question unanswered in the posted results.
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 principal limitation is that the primary tissue outcome was not analyzed: no participant underwent biopsy after study treatment. The registry record does not report why this occurred, whether baseline biopsies were obtained, or whether any alternative biomarker assessment was performed. Without post-treatment tissue measurements, the planned change in immunohistochemical scores cannot be estimated.
The single-group design provides no randomized comparator. Any observed change, had one been reported, would have lacked a concurrent control for distinguishing treatment-associated change from other explanations. The absence of masking is also recorded, but the registry does not say whether outcome assessors were blinded or how scoring consistency was evaluated.
The record does not report detailed participant characteristics, the number with cancer, actual treatment duration, adherence, or reasons for discontinuing treatment. It does not report endpoint results, statistical analyses, confidence intervals, p-values, analysis populations, missing-data methods, or a statistical analysis plan. The registry lists two outcome measures, but does not explain how multiplicity across proteins and time points was handled. Safety information is limited to aggregate participant counts; event descriptions and attribution are not reported. Deaths are not reported in the registry record.
These limitations constrain both biological interpretation and safety assessment. They do not show that the planned endpoint had no change or that treatment had no effect; they indicate that the posted results do not provide the measurements and analyses needed to assess those questions.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes — NCT00971789.
- Registry record last updated 2015-09-30; status last verified 2013-07.
- Results first posted 2013-07-19.
- 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
NCT00971789 is a completed phase 2 pilot study of sirolimus in people with Cowden syndrome or other PTEN hamartomatous tumor syndromes. It used a single-group design, had no masking, and enrolled 18 participants. The registry lists the study start as 2008-07 and primary completion as 2012-10, with the National Cancer Institute as sponsor.
The primary outcome was a planned immunohistochemical assessment of biochemical changes in benign and malignant tumor tissue at baseline, day 14, and day 56. The registry states that no participant underwent biopsy after study treatment, so no post-treatment tissue analysis was done. No statistical analyses are reported. The safety record lists 0 serious adverse events and 17 participants with other adverse events among 18 at risk; deaths are not reported in the registry record.