Estrogen and Fear in PTSD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Estrogen and Fear in PTSD (NCT04192266), a randomized phase 3 study. The primary outcome is Change in Amygdala Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal.

2. Clinical Question

The comparison concerns the added estradiol assignment within a PE therapy program, not estradiol as a stand-alone intervention. Both arms were assigned PE therapy, while the pill differed between arms. The stated purpose was to examine whether estradiol together with PE could improve treatment outcome in women diagnosed with PTSD, and to identify neural mechanisms associated with symptom reduction. The primary measure is a brain-activation outcome; PTSD symptoms and skin conductance response (SCR) were also included among the secondary outcomes.

The registry record describes a randomized, double-blind, placebo-controlled, multicenter study. The posted primary summary compares the average change in beta weights between the estradiol and placebo arms. That is a group-level contrast; it does not, by itself, establish why any difference occurred or whether it corresponds to a change that matters to participants. The registry record does not report further details on participant characteristics, such as age or PTSD history, so the population represented by the posted outcomes cannot be described more narrowly.

3. Trial Design

The registry classifies this as a phase 3, randomized, double-blind, parallel-group study. Its official title describes a placebo-controlled, multicenter study of neural mechanisms of PTSD symptom reduction associated with combined estrogen and prolonged exposure therapy. The registry lists the study as completed, an enrollment of 83, a start date of 2020-06-24, and a primary completion date of 2024-05-29. The brief summary describes 80 subjects planned across UTHealth Houston and UPenn, with 40 subjects at each site. The registry record does not explain the difference between planned enrollment and listed enrollment.

Participants were to be randomized to PE therapy with estradiol or PE therapy with placebo. According to the arm descriptions, the assigned pill was taken at home before each of 5 PE treatment sessions, specifically sessions 2 to 6. The brief summary describes preliminary screening and baseline visits, experimental visits, and therapy visits over the course of six weeks, followed by several follow-up visits. Further detail about the schedule or conduct of those visits is not reported in the registry record.

Double masking indicates that the study was described as double-blind, but the record does not say which specific groups or individuals were masked or how masking was maintained. The randomization sequence, allocation concealment procedures, and any stratification factors are not reported in the registry record. Nor does the record explain how participants were distributed between sites or provide a detailed account of the analysis population.

The planned design paired the same behavioral therapy with different pills, making the randomized contrast the addition of estradiol relative to placebo within the PE program. The registry record lists several outcome measures, but the available posted summaries include the primary outcome and summaries for SCR and CAPS. Statistical analyses for outcomes beyond those summaries are not reported in the registry 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.

Before assignment: A total of 123 participants were screened for eligibility. Of these, 83 participants met inclusion criteria and were enrolled in the study. Among the enrolled participants, 19 withdrew before randomization. The remaining 64 participants were randomized and began study participation.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data were not collected from 4 participants in the Prolonged Exposure (PE) Therapy With Active Pill arm because 3 participants dropped out and 1 participant had data acquisition errors. Data were not collected from 3 participants in the Prolonged Exposure (PE) Therapy With Placebo arm because 2 participants dropped out and 1 participant experienced an adverse event and the visit was not completed.

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 Change in Amygdala Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal, measured over Before and after treatment on Experimental day 2.

The primary endpoint is change in amygdala activation measured by fMRI BOLD signal, expressed in beta weights. The stated timeframe is before and after treatment on Experimental day 2. The registry description says the signal is assessed before and after completion of the experimental task. Positive beta weights indicate greater activation, and negative beta weights indicate less activation in the monitored brain region.

Using a continuous measure preserves information about the magnitude and direction of activation rather than reducing the result to categories. The posted arm summaries report mean change, with standard errors describing the precision of those estimated means. The comparison then expresses the difference between the group means. A positive mean difference in the posted contrast means the estradiol arm's mean beta-weight change is greater than the placebo arm's; it does not, without context, mean that activation is beneficial or harmful.

fMRI provides a way to quantify a neural response in a specified brain region during a task. That makes the endpoint relevant to a study whose stated purpose includes identifying neural mechanisms. It is nevertheless a neural measure, not a direct measure of PTSD symptoms or everyday functioning. The registry record does not report a threshold for a clinically meaningful change in beta weights, nor does it establish how a difference in this signal should be interpreted as a patient-important outcome. The clinical relevance of the primary contrast therefore cannot be inferred from its statistical estimate alone.

7. Results Posted in the Registry

• Prolonged Exposure (PE) Therapy With Estradiol: mean 0.53 versus -0.00 on control; difference 0.54 (95% CI 0.04 to 1.04), standardized effect d = 0.56; z-test p = 0.036.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Skin Conductance Response (SCR) During Recall

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Prolonged Exposure (PE) Therapy With Estradiol: mean -0.07 versus -0.20 on control; difference 0.12 (95% CI 0.07 to 0.17), standardized effect d = 1.64; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Prolonged Exposure (PE) Therapy With Estradiol than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Prolonged Exposure (PE) Therapy With Estradiol: mean -14.83 versus -18.23 on control; difference 3.40 (95% CI -1.72 to 8.52), standardized effect d = 0.35; z-test p = 0.193.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Prolonged Exposure (PE) Therapy With Estradiol and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes address different aspects of response: SCR during recall and change in PTSD symptoms measured with CAPS. Their overall pattern is mixed rather than uniformly aligned with the primary fMRI result. The available summaries include an unadjusted SCR comparison with an interval excluding zero and a CAPS comparison with an interval spanning zero. These are not interchangeable measurements, and a result on one does not establish the same pattern on another.

The SCR result relates to a physiological response during recall, while CAPS is a symptom measure assessed from baseline to 1 month post intervention. They complement the neural primary measure but answer different questions. Agreement across outcome types might add context, while disagreement can reflect differences in constructs, measurement, timing, or precision. The registry summaries alone do not identify which explanation accounts for the pattern.

The record lists five secondary outcomes, but the posted outcome summaries available for interpretation cover SCR and CAPS. The registry also lists multiple outcome measures and reports no analyses in its reported analyses list. As a result, the record does not establish that the two available summaries represent a complete set of planned secondary analyses.

Unadjusted secondary results carry less weight as confirmatory evidence when multiple outcomes are examined. In general, testing several outcomes without a reported multiplicity procedure increases the possibility that some results appear notable by chance. The registry record does not report a multiplicity adjustment, testing hierarchy, or complete prespecified analysis plan. The secondary results are therefore best treated as complementary, exploratory context for the primary contrast, rather than independent proof that the primary result reflects a broader or consistent treatment effect.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Skin Conductance Response (SCR) During Recall
• Skin Conductance Response (SCR) During Recall
• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)
• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)
• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean difference represent?

The primary outcome is continuous, so each arm is summarized by a mean. The mean difference compares the arm averages on their original measurement scale. In this comparison, the direction is estradiol minus placebo: positive values indicate a higher mean beta-weight change in the estradiol arm. The recalculated estimate uses the posted arm means. It is an unadjusted contrast and should not be confused with an adjusted analysis from a statistical model.

A mean difference retains the unit of the outcome, beta weights. This is useful because it preserves the scale used to measure the brain signal. Its interpretation still depends on what magnitude is meaningful in the context of the measure; a clinically meaningful threshold is not reported in the registry record. A standardized mean difference is also reported in the recalculation. It expresses the contrast relative to pooled variability, allowing scale-free description, but does not supply a clinical threshold.

What do standard errors and confidence intervals tell readers?

A standard error describes how precisely an estimated mean is determined, given the sample and the assumptions used for the calculation. It is not the same as the spread of individual participant values. The posted primary arm summaries use standard errors as their dispersion measure. A confidence interval describes a range of values compatible with the data and the method used to construct it; it reflects uncertainty in the estimated group contrast. It does not show the range of individual outcomes, and it is not a guarantee that the true effect falls within the interval.

The posted comparisons include unadjusted p-values. A p-value describes how unusual data at least as discrepant as those observed would be under a specified null hypothesis and statistical model. It does not measure the probability that the null hypothesis is true, nor the probability that the result will replicate. The registry record does not provide a detailed statistical analysis plan or identify a prespecified decision threshold for interpreting these tests.

Why is the primary comparison described as recalculated?

The reported contrast is recalculated from the posted summary statistics, using the arm means and standard errors. It is a simple, unadjusted calculation, not a substitute for a sponsor-reported analysis. No sponsor analysis for the primary contrast is listed in the registry record. The record also does not describe any covariates, repeated-measures model, or other adjustments that may have been considered. Because the discrepancy indicator is false, there is no recorded conflict between the posted summaries and a sponsor analysis for this comparison; that does not establish that the recalculation reproduces an unpublished analysis.

When summary estimates are used rather than individual participant data, the recalculation cannot inspect the distribution of observations, identify influential observations, or account for detailed features of the study design that are not in the record. The posted numbers permit a transparent group-level contrast, but they do not reveal all analytic decisions. The original statistical plan and the trial's own sample-size justification are not reported in the registry record.

Why can over-dispersion matter in general?

In general, over-dispersion occurs when observed variability is greater than a statistical model expects. A model that understates variability can produce standard errors that are too small and confidence intervals that are too narrow, making evidence appear more precise than it is. For continuous outcomes, the shape and spread of participant-level values can affect the suitability of model assumptions. The registry record does not report participant-level data or diagnostics that would allow an assessment of distributional assumptions or over-dispersion for these outcomes. This is a general methodological consideration, not a finding about this trial.

How should multiple outcomes be considered?

The registry record lists multiple outcomes, and the posted summaries include more than one comparison. When many hypotheses are tested, the chance of at least one apparently unusual result can increase if all tests are interpreted separately without accounting for multiplicity. In general, a prespecified hierarchy or multiplicity adjustment can help control that issue. Neither a hierarchy nor an adjustment is reported in the registry record. Consequently, secondary p-values should be viewed as unadjusted descriptive evidence rather than as a set of independently confirmed findings.

The registry lists nine outcome measures and five secondary outcomes. Its reported analyses list is empty, and no analyses are reported in the record. This limits the ability to determine whether the displayed outcomes reflect all planned analyses, whether other model specifications were used, or how missing observations were treated. A complete statistical interpretation would require details not reported in the registry record, including the analysis population, handling of missing data, and the prespecified analytic approach.

11. Confidence Intervals and Precision

The primary estimated mean difference is 0.538 beta weights, with a 95% confidence interval from 0.035 to 1.04. The interval is entirely above zero but extends from a small positive difference to a substantially larger one on the beta-weight scale. The point estimate alone would conceal this uncertainty. The interval is the more informative account of the range of values compatible with the unadjusted comparison and its assumptions.

Precision depends in part on the amount of information in the outcome data and the variability in the measure. The primary summaries include 27 participants in the estradiol arm and 30 in the placebo arm. These are the numbers associated with the posted primary outcome summaries, not necessarily the full randomized groups. The primary outcome description states that data were not collected from 4 participants in the active-pill arm because 3 participants dropped out and 1 participant had data acquisition errors. For the placebo arm, the description states that data were not collected from 3 participants; the reason is truncated in the registry record and is not reported in the registry record in full.

The interval's lower endpoint is close to zero, so modest changes in the estimate or its uncertainty could affect whether the interval includes zero. That does not establish that the result is fragile, but it underscores the importance of the missing details about analysis choices and missing observations. The unadjusted p-value and confidence interval are two related summaries of the same comparison, not independent pieces of evidence.

A confidence interval is not a prediction interval for individual participants and does not show the full range of possible responses. It also does not account for uncertainty from unreported design choices, selective reporting, or unreported multiplicity procedures. The registry record does not give a clinically meaningful threshold for the beta-weight measure, so the interval cannot be classified as excluding or including such a threshold.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect in each comparison, not the trial's original design calculation. For these continuous-outcome comparisons, the entries are participants per arm, not total events. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect.

The column for 80% power gives the estimated number of participants per arm for a hypothetical study to have an 80% chance of detecting the specified effect under those assumptions, if that effect and the assumptions are correct. The 90% power column uses a higher target chance of detection and therefore generally requires more participants per arm. These figures are not observed power. They do not describe the chance that the completed trial's result is true, nor do they assess whether the trial was adequately designed for outcomes other than the comparison used in the illustration.

The rows that plan for 100% of the observed effect use the full point estimate from the relevant posted comparison. Rows planning for 75% or 50% of the observed effect consider smaller target effects. Smaller effects are harder to distinguish from sampling variability, so they require more participants per arm under the stated planning assumptions. These are planning illustrations, not recommendations or a reconstruction of the original protocol.

The trial's original sample-size justification, chosen target effect, and original design assumptions are not reported in the registry record. Therefore, the illustrations should not be used to infer what the investigators planned or whether the completed enrollment met an original target. They show how hypothetical sample requirements change when the target effect is reduced while holding the listed assumptions in place.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.538; pooled standard deviation σ = 0.957.
2. n = 2 × (1.96 + 0.842)² × 0.957² / 0.538² = 49.7, rounded up to 50 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.5377                      # observed difference in means
sigma <- 0.956850629551304                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4192266)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 50 (80% power), 67 (90% power)
 75% of observed effect: n per arm = 89 (80% power), 119 (90% power)
 50% of observed effect: n per arm = 199 (80% power), 267 (90% power)
power.t.test: 50.7 
Simulated power at n = 50 per arm: 0.793 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

Several outcomes are registered, and multiple outcome summaries are posted. Repeated testing creates a multiplicity concern: when many hypotheses are evaluated, some can appear unusual by chance even if no underlying group difference exists. Statistical practice can address this through prespecified outcome hierarchies, family-wise error control, or other planned approaches. Which method is appropriate depends on the aims and design. The registry record does not report a multiplicity strategy, a hierarchy for interpreting primary and secondary outcomes, or whether any adjustments were applied.

The primary contrast is presented as an unadjusted recalculation from arm-level means and standard errors. The record does not provide a sponsor-reported analysis for it, a detailed analysis plan, or a description of covariate adjustment. It also does not report the trial's original sample-size justification or interim analyses. These details cannot be inferred from the posted results.

Missing outcome data are relevant to interpretation. For the primary outcome, the record says data were not collected from 4 participants in the estradiol arm, including 3 dropouts and 1 participant with data acquisition errors. It says data were not collected from 3 participants in the placebo arm, but the remainder of the reason is cut off; the full reason is not reported in the registry record. The available outcome summaries have fewer observations than the listed enrollment. The record does not describe whether missingness was related to outcome values or how missing observations were handled in the primary analysis.

Different outcome summaries also have different arm-specific sample sizes. The record does not explain all differences in the number of observations across measures, whether participants with incomplete outcomes were excluded from particular analyses, or whether imputation or sensitivity analyses were used. The analysis population—such as whether the analysis followed an intention-to-treat principle—is not reported in the registry record. These omissions limit assessment of the potential effect of missingness and the robustness of the findings.

These reporting gaps do not establish that the analyses were inappropriate. They mean that the posted summaries alone are insufficient to evaluate multiplicity control, missing-data assumptions, or fidelity to a prespecified statistical plan.

15. 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 reports serious adverse events affecting 0 participants in the PE therapy with estradiol group and 0 participants in the PE therapy with placebo group. The corresponding groups at risk for serious adverse events are listed as 31 and 33. Deaths are reported as 0 in each group. No serious adverse event terms are listed.

Other adverse events are reported as affecting 17 participants in the estradiol group and 18 in the placebo group; the groups at risk for other adverse events are listed as 31 and 33. These are counts, not rates, and they do not indicate whether an event was caused by the pill, the therapy, or another factor. The record does not provide event-level descriptions or timing in the safety summary, and it does not report a causal assessment for individual events.

Zero reported serious-event counts should be read as the registry's posted count for this study, not as proof that serious harms are impossible. The safety figures do not establish comparative safety beyond the events recorded and the study population described.

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

The primary estimate describes a difference in average change in amygdala BOLD activation between randomized groups assigned to PE therapy with estradiol or placebo. Its positive direction indicates a higher mean beta-weight change in the estradiol arm under the posted contrast. The confidence interval gives an indication of statistical precision for that unadjusted estimate. Neither the direction nor the size of a neural signal alone establishes a benefit or harm for participants.

The trial's stated purpose included both treatment outcome and neural mechanisms. However, the primary endpoint is an fMRI measure, while CAPS is the outcome that directly assesses PTSD symptoms in the posted secondary summaries. The available registry information does not establish that a change in amygdala activation causes a change in symptoms, mediates a treatment effect, or predicts later outcomes. The summaries also do not establish whether changes in the neural measure correspond to improvements in daily life.

The estimated contrast is based on the posted summary data and is not a documented sponsor analysis. The record does not report the complete statistical plan, missing-data methods, or multiplicity procedures. Those omissions limit the strength of conclusions that can be drawn from an unadjusted p-value, especially when several outcomes are listed. The secondary results provide context but do not resolve these uncertainties.

The randomized, double-blind, placebo-controlled design is relevant to comparing the assigned study arms. Still, the information available does not answer every question about bias, adherence, masking, or analysis populations. The posted findings apply to the trial participants and outcomes described; the record does not provide sufficient detail to assess how well they generalize to other populations or settings.

Accordingly, the result should be read as an observed, uncertain group contrast in a specific neural endpoint. It does not establish that estradiol improves PTSD, that it has no effect, or that the same pattern would occur in other settings. It also cannot replace a patient-centered interpretation of symptom and functional outcomes.

17. Why This Trial Matters Statistically

This trial is statistically interesting because it places a neural measure alongside a behavioral therapy and a placebo-controlled pill comparison. The design asks about the added estradiol assignment within PE therapy, while the primary endpoint quantifies a task-related brain signal. That combination makes it important to distinguish a measurable neural contrast from a clinical outcome and to avoid treating one as a proxy for the other without evidence.

The posted primary difference is positive, and its interval is above zero but relatively close to the null value at its lower end. That makes precision and analysis transparency central to interpretation. A point estimate without its interval would give an incomplete view, while an unadjusted p-value cannot address missing data, unreported model choices, or testing across multiple outcomes.

The record also illustrates why sample-size planning based on observed effects should be read cautiously. The planning figures change when the target effect is made smaller, emphasizing that a study's ability to detect modest effects can require a larger sample. These illustrations are distinct from the trial's original design assumptions, which are not reported.

Finally, the combination of neural, physiological, and symptom outcomes provides several perspectives, but the registry record does not report a complete analysis plan or multiplicity strategy. The statistical contribution is therefore not just the estimated contrast; it is also the need to interpret that estimate in light of what the registry does and does not document.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary outcome summary includes fewer participants than the registry's listed enrollment. The record identifies dropout and data acquisition errors among reasons for missing primary data in the estradiol arm, but the placebo-arm explanation is truncated. It does not describe the handling of missing data, the analysis population, or sensitivity analyses. These gaps make it difficult to assess whether the available summaries could be affected by missingness.

The posted primary comparison is an unadjusted recalculation from summary statistics, and the registry record does not list a sponsor analysis for that contrast. The original statistical analysis plan, covariate adjustments, interim analyses, and trial-specific sample-size justification are not reported. Nor is a multiplicity procedure or secondary-outcome hierarchy described. These limits make it difficult to determine how closely the displayed comparisons follow prespecified methods.

The outcome measures address different constructs and timeframes. The primary endpoint is a neural signal; secondary summaries include physiological response and PTSD symptoms. The record does not provide a clinically meaningful threshold for the primary measure or explain the relationship between neural change and patient-important outcomes. The posted summaries cannot establish a mechanism linking the outcomes.

The intended population is women diagnosed with PTSD, and the study was described as multicenter at UTHealth Houston and UPenn. The registry does not report detailed demographic or clinical characteristics, site-specific results, or enough information to judge generalizability. Masking is described as double, but who was masked and how masking was maintained are not reported in the registry record.

These limitations identify uncertainty in the available record; they do not demonstrate that the study was conducted improperly.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Estrogen and Fear in PTSD — NCT04192266.
• Registry record last updated 2026-01-09; status last verified 2026-01.
• Results first posted 2026-01-09.
• 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.

22. Record Summary

NCT04192266 is a completed phase 3, randomized, double-blind, parallel-group study of PE therapy with estradiol versus PE therapy with placebo in women diagnosed with PTSD. The registry lists enrollment of 83 and dates from 2020-06-24 to primary completion on 2024-05-29. The brief summary describes 80 planned subjects across UTHealth Houston and UPenn.

The primary endpoint is change in amygdala activation measured by fMRI BOLD signal in beta weights. The posted summaries yield an unadjusted mean difference of 0.538, with a 95% confidence interval of 0.035 to 1.04 and an unadjusted p-value of 0.036. Available secondary summaries cover SCR and CAPS. No sponsor analyses are listed, and the registry record does not report key details about multiplicity, the original analysis plan, or missing-data methods. Serious adverse events and deaths are reported as 0 in both groups.