Aging and Estrogen on Cortical Function: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Aging and Estrogen on Cortical Function (NCT01268046), a randomized phase 1, phase 2 study. The primary outcome is Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC).

2. Clinical Question

The endpoint is a brain-imaging measure rather than a direct measure of memory performance. The registry record describes a positive change as increased oxygen utilization during the task, interpreted as increased neuronal functioning, and a negative change as decreased oxygen utilization. That interpretation is the stated meaning of the signal; it does not establish that the signal change corresponds to a benefit or harm in everyday cognition.

3. Trial Design

The registry record describes a randomized, quadruple-masked, parallel-group study in phase 1 and phase 2. It lists enrollment of 38 and a completed status. The recorded start is 2009-11, and primary completion is dated 2013-12-02. The record does not specify the randomization sequence, concealment procedures, or which roles were included in quadruple masking.

Four groups are reported: young postmenopausal women assigned to estrogen, older postmenopausal women assigned to estrogen, young postmenopausal women assigned to placebo, and older postmenopausal women assigned to placebo. Estrogen could be delivered as a patch or oral capsule, while placebo could be delivered as a patch or oral capsule. The record does not say whether participants were randomized separately within age groups, how treatment formulation was allocated, or whether the formulations were compared.

The primary outcome was change in DLPFC fMRI signal from baseline to one month during an N-back task. The outcome population was participants who completed one month of treatment and had structural and functional MRI data of sufficient quality for analysis. The posted arm counts for this outcome are 12.0, 9.0, 7.0, and 7.0, respectively. These are outcome-group counts and should not be assumed to account for every enrolled participant.

The registry record does not report a sample-size justification, planned analysis details, or the rationale for the age-group definitions. It also does not describe adherence, treatment discontinuation, or the handling of participants who lacked usable imaging.

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: all young and older postmenopausal women who completed one month of placebo or estrogen and in whom structural and functional MRI data were of significant quality for 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 Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC), measured over baseline to 1 month.

The primary endpoint is the change in extracted beta coefficients of the blood oxygen level dependent signal in the dorsolateral pre-frontal cortex, from baseline to one month. The signal was recorded during an N-back cognitive task, and the reported unit is linear beta extractions. The coordinate identifying the region is listed as -34 44 16. The outcome is summarized as a mean with a standard error for each group.

Functional MRI is used in this study to quantify task-related brain activation rather than to count correct responses or directly measure memory in daily life. The registry description interprets a positive change as increased oxygen utilization, inferring increased neuronal functioning, and a negative change as decreased oxygen utilization between baseline and treatment during the task. These are interpretations of the imaging signal, not direct evidence of cognitive improvement or decline.

The endpoint was chosen to address the study’s focus on estrogen, aging, and cortical function. A change measure compares the imaging response at two time points, but the posted group summaries alone do not show each participant’s trajectory or establish what caused a group’s mean change. Details about task performance, imaging acquisition, beta extraction, or validation procedures are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a group mean describe?

A mean summarizes the average value of a continuous outcome across the participants included in a group. In this study, the outcome is change in extracted beta coefficients between baseline and one month. A positive mean and a negative mean describe opposite directions of average change under the registry’s signal interpretation. A group mean does not show whether all participants changed in the same direction, how widely individual changes varied, or whether a small number of observations influenced the average.

The four means should be read alongside their group counts and standard errors. The registry lists 12.0 participants in the young estrogen group, 9.0 in the older estrogen group, 7.0 in the young placebo group, and 7.0 in the older placebo group. These counts refer to the reported outcome groups. They are not necessarily the full randomized sample, because the outcome population required completion of one month and MRI data of sufficient quality.

What does the standard error mean?

In general, a standard error describes the precision of an estimated mean. It reflects how much the estimate would be expected to vary across repeated samples under the assumptions of the statistical procedure. A smaller standard error usually indicates a more precise estimate; a larger one indicates greater uncertainty. It is not the same as the standard deviation, which describes variation among individual observations.

The reported standard errors are 164.3, 90.1, 215.3, and 215.3 for the four groups in the order described. They help convey uncertainty around each group mean, but they do not directly quantify uncertainty in a difference between groups. Such a contrast also depends on the analysis method and the relationship between observations. The registry does not post confidence intervals or model-based contrast estimates, so those cannot be inferred from the group summaries alone.

Why compare treatment groups within age groups?

The study question concerns estrogen and age. A treatment comparison within each age group would address how the estrogen group’s outcome relates to the corresponding placebo group. Comparing those treatment contrasts across age groups would address whether the treatment pattern differs with age. In general, this latter question is an interaction question. It requires a defined statistical model and an estimate of the interaction, with uncertainty. The four means are useful descriptive information, but they do not substitute for such an analysis.

The registry record does not list an analysis of these contrasts. It also does not specify covariate adjustment, baseline adjustment, a repeated-measures model, or a method for accounting for the design’s age and treatment structure. Those details are not reported in the registry record. Consequently, the summaries should not be read as adjusted treatment effects or as evidence from a prespecified inferential model.

Why can variability matter for a continuous imaging outcome?

In general, continuous outcomes can have more variability than a simple model assumes. If the spread of observations is greater than expected, an analysis that assumes lower variability may understate uncertainty and produce confidence intervals or tests that are too optimistic. This is one reason analysts examine the outcome distribution and the assumptions of the chosen model. The registry record does not provide individual observations, distributional summaries, diagnostic results, or model details, so the adequacy of any particular variance assumption cannot be assessed.

The endpoint is an extracted imaging measure, and the registry’s analysis population depends partly on MRI data quality. Imaging measurements can require processing and quality decisions, but the specific procedures used in this study are not reported in the registry record. No claim about their reliability or potential influence on the results can be made from the posted summaries.

What can be said about statistical significance and planning?

No p-values, confidence intervals, or formal analysis results for the primary outcome are posted. The record lists 0 analyses. The observed group means and standard errors therefore do not establish whether a treatment contrast or age-related interaction is statistically distinguishable from uncertainty. Statistical significance, even if reported, would not by itself establish clinical importance.

In general, sample-size planning estimates the number of participants needed to detect a specified effect under assumptions about variability, allocation, and the significance level. Such calculations are planning illustrations, not evidence that a completed trial had a particular probability of finding an effect. The registry record does not report the trial’s own sample-size justification or analysis assumptions. The reported enrollment of 38 and outcome-group counts describe the trial record; they do not establish adequate power for any particular comparison.

The registry record gives no basis for reconstructing inferential tests from the arm summaries. Recalculating contrasts would require choices about the estimand, variance assumptions, and analysis population, none of which is specified sufficiently for a confirmatory result. The appropriate reading remains descriptive unless a complete analysis plan and results are available.

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("Young Postmenopausal Women - Estrogen", "Older Postmenopausal Women - Estrogen", "Young Postmenopausal Women - Placebo", "Older Postmenopausal Women - Placebo")
n   <- c(12, 9, 7, 7)
m   <- c(455.8, -214.4, -348.1, 90.1)
sp  <- c(164.3, 90.1, 215.3, 215.3)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
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  Young Postmenopausal Women - Estrogen  12  455.800  569.152  94.178  817.422
CARM  Older Postmenopausal Women - Estrogen  9  -214.400  270.300  -422.171  -6.629
CARM  Young Postmenopausal Women - Placebo  7  -348.100  569.630  -874.920  178.720
CARM  Older Postmenopausal Women - Placebo  7  90.100  569.630  -436.720  616.920

11. Multiplicity, Missing Data and Analysis Populations

The study describes questions involving treatment, age, and cortical function, but the registry record lists one outcome measure and no analyses. It lists no secondary outcomes. The number of hypotheses planned, the testing hierarchy, and any multiplicity adjustment are not reported in the registry record. Without those details, it is not possible to determine how the investigators intended to control the chance of false-positive findings across comparisons or outcomes.

The primary outcome itself involves four groups, and potential questions could include treatment comparisons within age groups and whether those comparisons differ by age. The registry does not identify which contrasts were prespecified or provide inferential estimates for them. It would be inappropriate to treat a descriptive pattern across the means as a selected, statistically tested result.

The stated outcome population includes participants who completed one month of placebo or estrogen and whose structural and functional MRI data were of significant quality for analysis. The registry record does not report how many randomized participants did not meet those criteria, why records were unavailable or excluded, or how missing endpoint data were handled. It does not report an intention-to-treat analysis, imputation, sensitivity analysis, or comparison of included and excluded participants. These omissions make it difficult to assess whether the reported outcome population differs systematically from the randomized population.

Although enrollment is listed as 38, the four outcome groups have different reported counts. The record does not explain the flow from enrollment to outcome analysis. It also does not report whether missingness arose from withdrawal, incomplete treatment, unusable imaging, or another cause. These details matter because selective availability of imaging data can affect how representative the group means are.

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 lists serious adverse events separately from other adverse events for the four reported groups. The number of participants affected by serious adverse events was 0 in each group: young estrogen, older estrogen, young placebo, and older placebo. Deaths were also listed as 0 in each group. No serious adverse event terms are listed.

For other adverse events, the counts affected were 1 among 12 at risk in the young estrogen group, 2 among 9 at risk in the older estrogen group, 1 among 7 at risk in the young placebo group, and 1 among 7 at risk in the older placebo group. These are participant counts, not event rates calculated. The registry does not describe the nature, severity, timing, or relatedness of these other events.

A zero count means that no affected participants are recorded in the registry for that group; it does not show that an event is impossible or that there is no risk. With relatively small group counts, the record provides limited information about uncommon harms. The listed at-risk counts are the safety denominators and should not be confused with a comprehensive safety assessment. Further details about safety monitoring and event collection are not reported in the registry record.

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

The posted results describe average changes in an fMRI measure during an N-back task in four groups of postmenopausal women. They show positive mean changes in the young estrogen and older placebo groups, and negative mean changes in the older estrogen and young placebo groups. The standard errors and group counts convey that these are estimates based on limited outcome samples, with uncertainty that varies across groups.

These data do not establish that estrogen increases or decreases cortical function. The endpoint is a task-related imaging signal, and its interpretation as oxygen utilization and inferred neuronal functioning does not directly measure memory ability or everyday functioning. The registry does not report a formal comparison, confidence interval, or p-value for the primary outcome. It also does not report an analysis testing whether the treatment pattern differs by age.

The results do not determine whether a patch and an oral capsule have equivalent effects, because their allocation and separate outcomes are not reported. Nor do they establish an effect beyond the one-month endpoint timeframe. The record does not provide longer-term imaging or clinical outcomes. The placebo groups offer descriptive context, but the posted means alone are not a substitute for an inferential comparison.

The study is recorded as completed, but a completed status does not by itself indicate that every enrolled participant contributed primary outcome data or that the outcome was analyzed as planned. The registry’s analysis population requires treatment completion and MRI data quality, and the reasons for differences between enrollment and outcome counts are not reported. The conclusions supported by the registry are therefore limited to the four reported group summaries and the stated outcome definition.

14. Why This Trial Matters Statistically

This trial is statistically interesting because its question combines a treatment comparison with age. Those are distinct components of an analysis: one asks how estrogen relates to the placebo condition within an age group, while another asks whether that relationship differs between age groups. The four group means make the structure of the question visible, but answering it requires estimates of contrasts and their uncertainty. The registry record does not provide those analyses.

The primary outcome is also a continuous imaging measure. Reporting a mean and standard error helps distinguish the estimated average change from its precision. That distinction is important when the observed group means have different directions and the group counts are limited. A descriptive pattern can motivate questions, but it should not be mistaken for a definitive treatment or interaction result.

The trial record highlights the importance of defining the analysis population for imaging outcomes. The stated population excludes participants who did not complete one month or whose MRI data did not meet quality requirements. Without participant flow and missing-data details, readers cannot evaluate the possible effect of those exclusions on the reported estimates.

Finally, the record is a reminder that a registered clinical question and posted arm summaries are not the same as a complete statistical report. The absence of posted analyses, confidence intervals, and comparison estimates constrains what can be concluded. Clear reporting of planned contrasts, analysis methods, missing-data handling, and uncertainty would be needed to evaluate the treatment-by-age question more fully.

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.

Several limitations are specific to the information recorded for this trial. The age categories are labelled young and older, but their cutoffs are not reported in the registry record. Further demographic and clinical characteristics of participants are also not reported. This restricts assessment of how the groups were defined and to whom the findings may apply.

The intervention descriptions allow either an estrogen patch or oral capsule, and the placebo descriptions allow either a patch or capsule. The registry record does not explain how formulation was chosen, whether formulations were balanced between groups, or whether route-specific outcomes were evaluated. Dose details are not reported. Accordingly, the arm summaries cannot be interpreted as a comparison of delivery routes.

The primary outcome depends on completion of one month and MRI data meeting quality criteria. The registry record does not provide participant flow, reasons for missing or excluded imaging, adherence information, or sensitivity analyses. It also does not report details of image processing, task performance, or statistical modeling. These omissions limit assessment of the reliability and representativeness of the estimates.

Only group means, standard errors, and outcome counts are posted for the primary outcome. Formal contrast estimates, confidence intervals, p-values, and analysis details are not reported in the registry record. The record also lists no analyses and no secondary outcomes. As a result, the magnitude and precision of treatment and age comparisons cannot be evaluated inferentially from the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Aging and Estrogen on Cortical Function — NCT01268046.
• Registry record last updated 2018-08-22; status last verified 2018-07.
• Results first posted 2018-08-22.
• 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 randomized, quadruple-masked, parallel-group phase 1 and phase 2 study of estrogen and placebo in young and older postmenopausal women. Enrollment was 38, and the study status is completed. The primary outcome was change from baseline to one month in DLPFC fMRI signal during an N-back task.

Four group means are reported, each with a standard error and outcome-group count. The outcome population required completion of one month and MRI data of sufficient quality. The registry lists no analyses, and it does not post inferential comparisons, confidence intervals, or p-values for the primary outcome. Safety listings report no serious adverse events or deaths in the groups, alongside small counts of other affected participants. The record supports descriptive interpretation but does not resolve the treatment-by-age question.