Early Menopause Hormone Treatment and Cognition: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Early Menopause Hormone Treatment and Cognition (NCT01046643), a randomized na study. The primary outcome is Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, quadruple-masked crossover study with enrollment of 30. The listed phase is NA, and the study status is COMPLETED. The sponsor is the University of Michigan. The study start is recorded as 2010-05 and primary completion as 2012-03.

The four arm descriptions represent treatment sequences: estrogen followed by placebo, progesterone followed by placebo, placebo followed by estrogen, and placebo followed by progesterone. This sequence structure is consistent with the record’s crossover classification: participants were assigned to sequences that included treatment and placebo rather than to a single treatment-only group. The record does not report the sequence allocation counts, how randomization was generated or concealed, or whether the four sequences had equal enrollment.

Quadruple masking indicates that the registry labels the study as masked at four levels, but the identities of the masked parties and the procedures used to maintain masking are not reported in the registry record. The length of each treatment period, the interval between periods, adherence procedures, and the precise schedule of assessments are also not reported. These details can matter when interpreting crossover comparisons because outcomes may depend on treatment order, time, or effects that persist between periods; whether those issues were addressed in this trial is not reported.

The primary outcome was changes in brain activation patterns in verbal tasks, assessed with fMRI. The study also listed verbal learning retention and visual learning retention among secondary outcomes. The brief description gives a broader objective involving neuropsychological tests, episodic memory challenges, and emotional processing. The registry record lists four outcome measures and 16 analyses, but it does not identify the full set of analysis specifications in the information available for this account.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Several enrolled participants were excluded from the trial prior to assignment in groups on the basis of the risk factors identified at the pre-screening appointment. Some others did not qualify due to their lab results which did not meet the inclusion criteria.

First Period Treatment or Placebo

Reasons for not completing this period:

Washout Period

Second Period Treatment or Placebo

Analysis population for the primary outcome, as defined in the registry: Within the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events, and in the Progesterone/Placebo groups, 1 participant's fMRI scans were damaged and unable to be used in the analysis.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans, measured over August 2010 - March 2012.

The primary endpoint concerns changes in brain activity during verbal tasks, expressed as percent BOLD signal changes measured with functional magnetic resonance imaging. BOLD is a functional imaging signal used to assess brain responses associated with a task. As a general explanation, a signal contrast between task conditions can help characterize whether brain activation patterns differ across conditions; the registry record does not report the particular contrasts or regions used for its primary analysis.

The verbal task included shallow processing, in which participants judged whether a word was written in upper or lower case, and deep processing, in which they judged whether a word represented an abstract or concrete concept. Participants saw lists of words one word at a time and made one of these two decisions. This design uses tasks that differ in the kind of processing required, allowing researchers to examine brain responses during verbal processing rather than relying only on a general cognitive score.

The outcome description states that testing occurred 3 months after baseline and 38 weeks after baseline. The timeframe for the outcome is August 2010 - March 2012. The record does not report the numerical activation results, the exact endpoint contrasts, or the regions analyzed. It also does not give a single reduced comparison because the primary outcome has several categories or time points. The rationale for selecting this imaging endpoint over other cognitive measures is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a continuous primary measure, describes its parameter as a mean, and identifies standard deviation as its dispersion measure. It does not report the statistical model, the estimated treatment contrasts, or inferential results. The following concepts are general explanations and are not claims about analyses actually performed in this trial.

What does a mean describe?

For a continuous outcome such as percent BOLD signal changes, a mean is an average across the measurements included in a particular group, condition, or analysis. Its interpretation depends on which participants and observations contributed to it and on how the endpoint was constructed. The registry record does not provide the numerical means or the exact definition of each analyzed contrast, so the outcome scale alone does not reveal the observed treatment effect.

A standard deviation describes variability among measurements around a mean. It is not the same as a standard error or a confidence interval. A standard deviation characterizes the spread of the observed values; a standard error characterizes the uncertainty in an estimated quantity under a statistical model. A confidence interval communicates uncertainty around an estimate by giving a range of values compatible with the data and assumptions. The registry record reports no numerical standard deviations or confidence intervals for the primary endpoint.

How does a crossover comparison differ?

In a crossover study, treatment sequences include more than one condition, and participants may contribute measurements under different conditions. A general analysis can account for the pairing of observations within participants, rather than treating every observation as independent. This can be useful because stable participant characteristics may affect measurements in both conditions. It also means that an analysis generally needs to represent the repeated-measures structure appropriately.

Period and sequence can matter in crossover designs. A period effect is a change associated with when a measurement occurs, regardless of the treatment received. A sequence effect is a difference associated with the order in which conditions are assigned. Carryover refers, in general, to an effect of an earlier treatment that remains relevant during a later period. The registry record does not report the treatment-period durations, washout interval, or analysis of period, sequence, or carryover. It therefore does not establish whether these features were modeled or how they may affect interpretation.

Why does the endpoint have multiple components?

The verbal task includes shallow and deep processing, and the outcome is assessed at the stated time points of 3 months after baseline and 38 weeks after baseline. Different task conditions, time points, or brain regions can yield distinct comparisons. The record states that the primary outcome has several categories or time points and was not reduced to one comparison. Without the full analysis plan, it is not possible to identify which contrasts were prespecified, how they were prioritized, or whether multiplicity adjustments were used.

Multiplicity is a general issue when several statistical tests address related questions. If many tests are considered, the chance of at least one result appearing unusual under a null model can increase. Adjustments are one way to account for that, while a prespecified hierarchy or clearly exploratory interpretation can also clarify the evidential role of multiple analyses. No multiplicity procedure is reported in the registry record. The listed count of 16 analyses does not, on its own, identify the family of tests or the approach to controlling multiplicity.

What can a p-value and confidence interval say?

In general, a p-value describes how incompatible the observed data are with a specified null model, conditional on the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor does it measure the clinical or scientific importance of an effect. A confidence interval gives information about the range and precision of an estimate. These measures answer related but different questions, and both need to be interpreted in light of the outcome definition, design, and analysis. Neither a p-value nor a confidence interval for the primary outcome is reported in the registry record.

What does the planning illustration represent?

The registry record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. For time-to-event outcomes, such illustrations give a total number of events, while other outcomes are expressed as participants per arm. The registered primary measure is continuous, but no numerical planning results are reported in the registry information.

Such sample-size calculations are planning illustrations, not observed power. They do not show the probability that the completed trial detected an effect, and they do not replace the trial’s actual estimates and uncertainty. The original sample-size justification, the target effect used in the trial’s own design, and whether the planning assumptions match the original protocol are not reported in the registry record.

For this study, interpretation would require the endpoint estimates, the corresponding uncertainty, the analysis population, and the model used for the crossover measurements. It would also require enough detail to understand the multiple task conditions and assessment times. Those statistical details are not reported in the registry record, so general principles cannot identify the trial’s actual analysis or supply missing results.

10. Multiplicity, Missing Data and Analysis Populations

The record lists four outcome measures and 16 analyses. It identifies verbal learning retention and visual learning retention as secondary outcomes, while the primary outcome is fMRI activation during verbal tasks. The primary outcome is described as having several categories or time points and is not reduced to one comparison. The precise set of tests, their order of priority, and whether any multiplicity adjustment was used are not reported in the registry record.

Missing fMRI data are described for both treatment-sequence groupings. In the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events. In the Progesterone/Placebo groups, 1 participant's scans were damaged and could not be used in the analysis. The record does not report whether these participants contributed to other outcomes, how missing fMRI observations were handled, or whether any imputation or sensitivity analysis was used.

In general, missing outcome data can affect both the number of observations available and the interpretation of estimates, especially if missingness is related to participant characteristics or outcomes. In a crossover design, missing measurements in one period may also affect whether a participant contributes a within-person comparison. The registry record does not report the analysis population, the amount of missingness at each assessment, or the assumptions used for handling unavailable measurements. The reported enrollment of 30 should therefore not be taken as the number contributing to every outcome analysis.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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 record reports serious adverse events for each sequence group. It lists 0 affected among 9 at risk in Estrogen Followed by Placebo, 0 among 7 at risk in Progesterone Followed by Placebo, 0 among 7 at risk in Placebo Followed by Estrogen, and 0 among 7 at risk in Placebo Followed by Progesterone. No serious adverse event terms are listed. The record does not report death counts in the information.

The other adverse event counts are 1 among 9 at risk for Estrogen Followed by Placebo, 1 among 7 for Progesterone Followed by Placebo, 3 among 7 for Placebo Followed by Estrogen, and 1 among 7 for Placebo Followed by Progesterone. These are the registry’s group-specific counts; they do not establish that an event was caused by a study treatment. Because this is a crossover study with sequence groups, group counts should not automatically be read as independent parallel-treatment comparisons.

These figures describe reported events in the registry record, not the complete safety profile or comparative risk. The record does not include event descriptions for the other adverse events, their timing, severity, or relationship to treatment. A count of zero recorded serious adverse events does not by itself establish absence of risk.

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

This trial’s registry record documents a randomized, quadruple-masked crossover study of estradiol, progesterone, and placebo in healthy early postmenopausal women. It identifies a primary outcome focused on fMRI activation during verbal processing and gives the assessment timing and task description. It also identifies secondary neuropsychological outcomes and reports selected adverse event counts.

The record does not report numerical findings for the primary fMRI outcome. Without the estimates and their uncertainty, the direction and size of any treatment-placebo difference cannot be described. It is also not possible to assess whether the observed data are compatible with a range of effects, or whether estimates are precise. No conclusion about treatment effects on brain activation or cognitive testing should be inferred from the design description alone.

The study’s crossover structure and several outcome categories or time points make the analysis details particularly relevant. A reader would need to know how repeated observations were modeled, how treatment sequence and assessment period were addressed, and which contrasts were considered primary. The record does not report those details or any multiplicity procedure. The missing fMRI scans and unavailable analyses also mean that the enrolled number cannot be assumed to equal the number analyzed for every endpoint.

The adverse event counts are descriptive registry entries. They do not establish causation or provide a complete comparison of safety between treatments. The record gives no serious adverse event terms and no death counts in the information, but the absence of reported details is not evidence that unreported events did not occur.

Overall, the registry record establishes what the study set out to examine and how it was broadly organized, but it does not provide enough outcome or analysis information to quantify the findings. Results should be interpreted only when estimates, uncertainty, analysis populations, and methods are available, with attention to the crossover design and the multiple outcome components.

13. Why This Trial Matters Statistically

This study is statistically notable for combining a randomized crossover design with an imaging-based continuous outcome and several cognitive tasks. A crossover design can support within-participant comparisons in general, but interpretation depends on the handling of repeated measurements and the timing and order of treatment periods. The registry record does not provide those implementation or analysis details, making design transparency important for readers assessing the evidence.

The primary measure is percent BOLD signal changes during shallow and deep verbal processing, rather than a single general cognitive score. This makes the endpoint closely tied to task conditions and assessment times. Because the record identifies several categories or time points, it is important to distinguish prespecified contrasts from additional analyses and to understand how multiplicity was addressed. The number of analyses alone does not supply that information.

The record also illustrates why outcome availability matters in imaging studies. Some fMRI data could not be analyzed because participants were unable to complete required analyses or scans were damaged. Clear reporting of who contributed usable measurements and how unavailable data were handled is essential for interpreting estimates in a crossover setting.

Finally, a completed study record and a defined endpoint do not by themselves permit an effect-size or precision assessment. Without numerical results, uncertainty estimates, and a full analysis description, the statistical evidence cannot be characterized. The record’s value is therefore primarily in documenting the question, broad design, outcome definition, and specific gaps that limit interpretation.

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 main limitation for interpreting the trial statistically is that numerical results for the primary outcome are not reported in the registry record. Means, standard deviations, treatment contrasts, confidence intervals, and p-values are not available in the information. As a result, neither the direction nor precision of any fMRI finding can be assessed.

The endpoint covers multiple verbal-processing conditions and assessment times, and the record says it is not reduced to one comparison. The analysis plan, selected contrasts, and multiplicity approach are not reported. The record also does not report which brain regions or image-processing definitions were used, or how outcomes were summarized across them.

Details needed to evaluate the crossover analysis are also not reported. These include treatment-period durations, washout timing, sequence allocation counts, and the treatment of period, sequence, or carryover. The randomization procedures and the identities of the masked parties are not described. Without these details, the design label alone cannot establish how potential sources of bias were handled.

For the primary fMRI outcome, the record notes unavailable data in both treatment-sequence groupings: 3 participants could not complete the needed analyses due to adverse events, and 1 participant's scans were damaged. The extent and handling of missing data across each outcome and time point are not reported. The analysis population and any sensitivity analyses are also not reported.

The enrollment is 30, but the record does not state how many participants contributed to each endpoint analysis. It also does not provide the original sample-size justification or the protocol’s statistical analysis plan. These limitations prevent assessment of the planned precision, the distinction between confirmatory and exploratory analyses, and the robustness of any result.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Early Menopause Hormone Treatment and Cognition — NCT01046643.
• Registry record last updated 2014-05-19; status last verified 2014-05.
• Results first posted 2014-05-19.
• 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.

18. Record Summary

The University of Michigan study, NCT01046643, is titled “Early Menopause Hormone Treatment and Cognition,” with the official title “Hormones and Cognitive Processing in Early Postmenopausal Women.” It is listed as a completed, randomized, quadruple-masked crossover study with enrollment of 30 and phase NA. The recorded study start is 2010-05 and primary completion is 2012-03.

The primary outcome is change in brain activation during verbal tasks, measured as percent BOLD signal changes. The task involves shallow and deep verbal processing, with assessments 3 months after baseline and 38 weeks after baseline. Secondary outcomes include verbal learning retention and visual learning retention.

The registry record does not report numerical primary outcome findings or the detailed statistical analysis plan. It notes unavailable fMRI data for some participants and lists group-specific adverse event counts. The record therefore describes the study question and broad design but does not support an estimate of the primary treatment effect or its precision.