Endothelial Facilitation in Alzheimer's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Endothelial Facilitation in Alzheimer's Disease (NCT01439555), a na phase 2 study. The primary outcome is Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI).

2. Clinical Question

3. Trial Design

This is a Phase 2, open-label pilot study with a single-group model. The registry record identifies Alzheimer's disease as the condition and describes treatment with simvastatin, L-arginine and tetrahydrobiopterin. The sponsor is the University of Massachusetts, Worcester. The record gives a start date of 2011-11, a primary completion date of 2017-11, and a status of COMPLETED. It lists enrollment as 11.

Because the study has one treatment group and no listed comparator, its design can describe measurements collected during treatment but cannot, by itself, separate a treatment-related change from changes that might occur over time for other reasons. Open-label status also means masking was not used, according to the record. How participants were recruited, how treatment adherence was assessed, and whether there were protocol deviations are not reported in the registry record.

The brief summary describes giving the three drugs over a 4-month period. The primary outcome timeframe is stated as baseline to 16 weeks. These are the time descriptions recorded for the study; more detail about visit schedules or the timing of individual drug additions is not reported in the registry record. Although the official title describes sequential and cumulative effects, the registry record does not provide a detailed schedule for the sequence or a separate estimate for each treatment stage.

The primary outcome was mean change in cerebral blood flow on MRI. Listed secondary outcomes were MMSE, CAST, CDR, ADAS-COG and CIBIC Plus. The record lists 7 outcome measures and 0 analyses. It does not report numerical results for the primary or secondary outcomes, or provide an analysis plan explaining how they were evaluated. The primary-outcome description specifically states that data were available for 6 participants and that remaining participant files were corrupted and unavailable for analysis or reporting.

The record's sample-size assumptions describe a planning illustration using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. This is not a description of the actual single-group design. The effect to detect is specified as a stated fraction of an observed effect, but the registry record does not report the illustration's resulting sample-size values. These assumptions should not be read as the trial's own design rationale or as evidence of observed power.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data for 6 participants available. Data file for remaining participants corrupted and could not be retrieved for analysis/reporting.

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: Prospective, open-label, single group assignment, single center study conducted by UMass Medical School at the UMass Memorial Medical Center in Worcester, MA. 11 subjects total were screened and enrolled in this study, 10 subjects completed the study as 1 subject was initially enrolled but was excluded due to not meeting inclusion criteria.

6. Primary Endpoint

The registry lists the primary outcome as Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI), measured over Baseline to 16 weeks.

The primary endpoint is mean change in cerebral blood flow, measured by magnetic resonance imaging, from baseline to 16 weeks. The unit is ml/110g/min, and the outcome description refers to measurements in regions of interest. The record identifies the endpoint as a continuous measure summarized by a mean and standard deviation. It also states that cerebral blood-flow data were available for 6 participants; files for the remaining participants were corrupted and could not be retrieved for analysis or reporting.

Cerebral blood flow is a physiological measure of blood moving through brain tissue. In general, an imaging measure can be used to assess a biological process that a treatment is intended to affect. A before-and-after endpoint can show whether measured values differ over the study period among participants with data, but without a comparison group it cannot determine whether any change was caused by treatment rather than by other influences. This is a general limitation of interpreting change in a single group, not a conclusion about the direction or size of change in this study.

The registry record does not report the observed mean change, standard deviation, confidence interval, or a test result for this endpoint. It therefore does not establish the magnitude or precision of any change. The stated endpoint and the available-data note define what was intended to be measured and the extent of the reported data availability, but they do not supply a numerical efficacy result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help distinguish what this record can describe from what it cannot establish. The registry labels the primary outcome as continuous and identifies its summary measure as a mean with standard deviation. These labels describe a way to represent measurements; they do not provide the missing numerical result.

What does a mean change represent?

For a continuous outcome measured at baseline and follow-up, a participant's change is the follow-up value compared with that participant's baseline value. The mean change describes the average of those changes among the participants included in the analysis. It is not the same as comparing two unrelated groups' average values, and it does not show whether every participant changed in the same direction. Individual changes can vary around the mean.

The standard deviation describes how dispersed the observed values are around their mean. It is a measure of variability in the data, not a measure of how precisely the mean is estimated. The registry record identifies standard deviation as the dispersion measure for the primary outcome but does not report its value or the mean change. Without those values, the degree of observed variability cannot be examined.

What would a confidence interval add?

In general, a confidence interval gives a range of estimates compatible with the data and the statistical method used, expressing uncertainty around an estimate. A narrow interval indicates greater precision than a wide interval, under the same modeling assumptions. It does not guarantee that the true value lies within the reported interval in any one analysis, and it does not correct for design limitations or missing data. The registry record does not report a confidence interval for the primary outcome.

A confidence interval is especially useful alongside the point estimate because a test result alone does not show the size or precision of a possible change. Here, neither a point estimate nor an interval is reported. Therefore, readers cannot assess whether the data are compatible with little change, a larger change, or a range of possible effects. Those possibilities should not be treated as observed results.

Why does the single-group design matter?

A before-and-after analysis in a single group can describe change over time among participants with measurements. It cannot directly compare that change with what would have happened over the same period without the intervention. In general, a control group helps account for influences shared by the study period, while random allocation can help make groups comparable on average. This trial is recorded as a single-group study, with allocation listed as NA and masking listed as NONE; it does not provide a randomized, masked comparison.

Because the study was open label, participant and investigator expectations could potentially influence subjective measures or study procedures. The primary outcome is an MRI measurement, but the registry does not describe imaging procedures, reader masking or quality-control methods. Whether any such safeguards were used is not reported in the registry record. This is a limitation in assessing measurement procedures, not evidence that a specific source of bias occurred.

How should missing data be understood?

The primary-outcome description says that data for 6 participants were available and that files for the remaining participants were corrupted and could not be retrieved for analysis or reporting. This is a data-availability problem. In general, missing observations reduce the information available and can affect how representative an analysis is, particularly if the availability of data is related to participant characteristics or outcomes. The record does not report whether such relationships were assessed, nor does it describe imputation, sensitivity analyses or another method for addressing the unavailable files.

The record's enrollment figure and the primary-outcome availability statement are not interchangeable: one describes enrollment, while the other describes the availability of a particular outcome. The safety entries use their own at-risk figures. The registry record does not explain how the analysis populations for primary, secondary and safety outcomes were defined, so those counts should not be combined or treated as referring to identical sets of participants.

What does the planning illustration mean?

The registry record describes planning assumptions for a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. These are assumptions for a planning illustration, not a description of the trial's single-group design. The listed illustration does not provide numerical sample-size results in this record.

In general, a sample-size calculation explores how many participants per arm might be needed to detect a specified effect under stated assumptions. Its output depends on the assumed effect, variability, allocation, significance level and target power. A planning illustration based on an observed effect is not a measure of the probability that this completed study detected an effect. It must not be interpreted as observed power, nor as evidence that the trial was designed around those assumptions. The registry record does not report the trial's own sample-size justification or a statistical analysis plan.

Over-dispersion is a general concern when variation in observed data exceeds what a chosen statistical model assumes. If a model understates variability, uncertainty estimates can be too optimistic. The registry record does not report a model-based analysis of the primary endpoint, so there is no basis to say whether over-dispersion was assessed or relevant in this trial. More broadly, statistical methods can clarify uncertainty only when the analysis and its results are reported; the registry record lists 0 analyses and does not provide the numerical outcome estimates needed for that evaluation.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists several secondary cognitive measures: MMSE, CAST, CDR, ADAS-COG and CIBIC Plus. It also lists 7 outcome measures overall and 0 analyses. Numerical results for the secondary outcomes are not reported in the registry record. The record does not describe which outcomes were analyzed, how comparisons among outcomes were handled, or whether any multiplicity adjustment was planned or applied.

Multiplicity is a general issue that arises when several outcomes or statistical tests are considered. The more opportunities there are to identify an apparently notable result, the more important it is to distinguish a prespecified primary question from exploratory analyses and to account for the full testing context. This is a general explanation; the registry record does not establish that any particular multiplicity problem occurred. Without an analysis plan or reported tests, readers cannot evaluate how the listed outcomes were prioritized or interpreted.

Missing primary-outcome data are a specific concern: cerebral blood-flow data were available for 6 participants, while files for the remaining participants were corrupted and unavailable for analysis or reporting. The record does not report the method used to handle missing data, whether imputation or sensitivity analyses were performed, or whether data availability was related to participants' outcomes.

The registry record does not define analysis populations for the primary, secondary or safety outcomes. It does not report whether analyses followed an intention-to-treat principle, were limited to participants with available measurements, or used another population definition. These details are not reported in the registry record. The enrollment count, outcome-data availability and safety at-risk figures describe different record entries and should not be assumed to represent the same analysis population.

11. 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.

The registry record lists the treatment group as Simvastatin + L-Arginine + Tetrahydrobiopterin. For that group, 10 participants were at risk for serious adverse events and 0 serious adverse events were recorded. The same at-risk count and 0 events are listed for other adverse events, and deaths are recorded as 0. No serious adverse-event terms are listed.

These figures should be read as the safety counts recorded, not as proof that the regimen is free from risk. A zero count means that no events were recorded in that category in the listed safety data; it does not show how events were sought, classified or followed over time. The registry record does not report definitions, ascertainment procedures, event timing, or details on severity and relatedness. It also does not explain why the safety at-risk count differs from the study enrollment figure. The safety counts should not be treated as if they describe every enrolled participant unless the record establishes that link.

Safety findings from a small pilot study can provide descriptive information, but the available record does not support a broad estimate of event frequency or a comparison with another treatment. No control group is listed, and the event counts are not accompanied by further safety analyses.

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

The record establishes that a Phase 2, open-label, single-group pilot study examined a regimen of simvastatin, L-arginine and tetrahydrobiopterin in patients with mild Alzheimer's disease. It identifies MRI-measured mean change in cerebral blood flow from baseline to 16 weeks as the primary outcome and lists several cognitive measures as secondary outcomes. It also reports that primary-outcome data were available for 6 participants, while the remaining files were corrupted and unavailable for analysis or reporting.

The registry record does not report a numerical primary-outcome result, a confidence interval, a statistical test or numerical results for the secondary outcomes. Therefore, it does not show the direction, magnitude or precision of a change in cerebral blood flow or cognitive measures. The absence of these reported results should not be interpreted as evidence of no change, just as the study description alone cannot be taken as evidence of a beneficial change.

The single-group design can describe measurements over time, but it cannot establish what would have happened in a comparable group not receiving the regimen. Open-label status and the lack of a listed control group limit causal interpretation. Missing primary-outcome data further restrict what can be learned from the available measurements, and the record does not report analyses that address the missing files.

The safety entries show 0 serious adverse events, 0 other adverse events and 0 deaths among the at-risk counts recorded. They are descriptive entries, not a guarantee of safety. With no comparative safety group listed and no further details on how events were collected, the record does not establish comparative risk.

In general, results from a pilot study may inform the feasibility of measurement and help define questions for further research. The registry record does not report feasibility outcomes, a detailed statistical plan or a sample-size justification, so those aspects cannot be evaluated. The appropriate reading is limited to the design and data availability described, while recognizing that the central numerical outcome findings are not reported.

13. Why This Trial Matters Statistically

This study raises a useful statistical distinction between a biological question and the evidence needed to answer it. The stated primary question concerns change in cerebral blood flow during a multi-drug regimen. Measuring an imaging outcome over time can be informative, but the meaning of any observed change depends on its size, variability, precision and the design used to separate treatment effects from other influences. The registry record names the endpoint but does not report its numerical result.

The trial is also a reminder that data integrity is part of statistical interpretation. The record states that primary-outcome files for the remaining participants were corrupted and could not be retrieved for analysis or reporting. Missing measurements affect not only the amount of information but also the ability to assess whether the analyzed data represent the intended study population. The record does not describe additional analyses of this problem.

A single-group pilot design can be appropriate for descriptive or exploratory aims, but it does not yield a randomized treatment comparison. When the objective is to estimate a causal effect, the absence of a concurrent comparator limits what change over time can establish. This distinction is important when interpreting intervention studies that combine multiple components, because the design does not isolate the contribution of each drug.

Finally, a registry record's outcome definitions, data-availability notes and numerical results serve different purposes. Here, the endpoint is defined and the missing-data issue is described, while numerical outcome estimates and recorded analyses are absent. That combination makes clear why transparent reporting of estimates, uncertainty, analysis populations and missing-data methods is important: without them, readers cannot evaluate the size or 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 principal limitation for interpreting the study is that the registry record does not report numerical results for the primary outcome. It provides no mean change, standard deviation, confidence interval or test result for cerebral blood flow. Numerical results for the listed secondary cognitive outcomes are also not reported. The record lists 0 analyses, leaving no reported inferential results to assess.

Primary-outcome data were available for 6 participants; files for the remaining participants were corrupted and could not be retrieved for analysis or reporting. The record does not explain whether the unavailable data were assessed for systematic differences from the available data, or whether any sensitivity analysis was undertaken. This limits assessment of how the missing information affects the outcome estimate.

The single-group, open-label design has no listed control group or randomized comparison. It therefore cannot distinguish a treatment-associated change from other changes over the study period, nor isolate the effects of the individual drugs in the combination. The record's title refers to sequential and cumulative effects, but a detailed dosing sequence and separate stage-specific estimates are not reported.

The registry record does not report eligibility criteria beyond its description of patients with mild Alzheimer's disease, the imaging acquisition and analysis procedures, adherence, protocol deviations, or an analysis plan. It does not report the study's sample-size justification, a multiplicity approach, or defined analysis populations. These unreported details prevent fuller assessment of methods and potential sources of uncertainty.

Safety counts are recorded for 10 participants at risk, while study enrollment is listed as 11. The record does not explain the relationship between these counts or provide additional adverse-event collection details. These are limits of what can be interpreted from the registry record, not evidence about what occurred beyond the recorded entries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Endothelial Facilitation in Alzheimer's Disease — NCT01439555.
• Registry record last updated 2019-07-30; status last verified 2019-07.
• Results first posted 2019-07-30.
• 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.

18. Record Summary

NCT01439555 is a completed Phase 2, open-label, single-group pilot study sponsored by the University of Massachusetts, Worcester. The registry record lists Alzheimer's disease as the condition, enrollment of 11, a start date of 2011-11 and a primary completion date of 2017-11. The intervention group received simvastatin, L-arginine and tetrahydrobiopterin.

The primary outcome was mean change in MRI-measured cerebral blood flow from baseline to 16 weeks. Data were available for 6 participants; files for the remaining participants were corrupted and unavailable for analysis or reporting. A numerical primary-outcome estimate and numerical secondary-outcome results are not reported in the registry record. The record lists 7 outcome measures and 0 analyses.

Safety entries record 0 serious adverse events, 0 other adverse events and 0 deaths, with 10 participants at risk for the adverse-event categories. The single-group design has no listed comparator, and the registry record does not report a statistical analysis plan or numerical outcome estimates.