Optimal Treatment for Women With a Persisting Pregnancy of Unknown Location: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Optimal Treatment for Women With a Persisting Pregnancy of Unknown Location (NCT02152696), a randomized phase 3 study. The primary outcome is Number of Participants With Uneventful Clinical Resolution of a Pregnancy of Unknown Location Without Change From the Initial Management Strategy.

2. Clinical Question

The central statistical question is about the probability of reaching a defined clinical outcome under each assigned management strategy, not simply whether hCG declined. The outcome combines clinical resolution with completion without a change from the initial strategy. This makes it relevant to how consistently each strategy was followed through to resolution, while also making the result dependent on the definition of an uneventful course.

The trial was randomized and parallel, with allocation described as 1:1:1. The record identifies no masking. Because the management strategies differ in procedures, medication, and monitoring, the comparison concerns these complete strategies as described in the record; it does not isolate the effect of a single component. The registry record does not report further detail about eligibility criteria beyond the summary description, or information about how clinicians and participants made decisions to change management.

3. Trial Design

This phase 3 randomized clinical trial compared three management strategies for women with PPUL who were considered at risk for ectopic pregnancy. The registry lists Yale University as sponsor, an enrollment of 255, and a completed status. The recorded study start is 2014-07-25, with primary completion in 2019-08. These record details describe the trial’s registration and conduct timeline, but do not by themselves establish when the results were analyzed or posted.

Participants were allocated in a parallel design to expectant management, uterine evacuation with methotrexate for some, or empiric methotrexate for all. The allocation description states 1:1:1, and masking is listed as none. Expectant management involved serum hCG monitoring. In the uterine-evacuation strategy, methotrexate was used if hCG did not decrease sufficiently after evacuation; if it decreased sufficiently, no further treatment was required. In the empiric strategy, methotrexate was given on day 0 and day 4, with additional doses as needed based on hCG levels.

The summary says that participants would be followed and treated clinically as indicated by the progression of their condition. Thus, the assigned strategy was not necessarily a fixed sequence of care regardless of clinical course. The primary outcome captures whether resolution occurred without a change from the initial management strategy, making changes in management relevant to the outcome definition.

The primary outcome timeframe is 6 weeks from randomization. The record lists one outcome measure and no secondary outcomes posted. It lists no statistical analysis results count, although pairwise primary-outcome comparisons are posted. The registry record does not report the original sample-size justification, detailed analysis plan, allocation concealment procedures, or reasons for changes from assigned management.

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

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 Number of Participants With Uneventful Clinical Resolution of a Pregnancy of Unknown Location Without Change From the Initial Management Strategy, measured over 6 weeks from randomization.

The primary endpoint counts participants with uneventful clinical resolution of a pregnancy of unknown location without a change from the initial management strategy. Its timeframe is 6 weeks from randomization. The measure is reported as a count of participants in each arm, so each participant either contributes to the reported event count or does not.

The endpoint is used to represent a resolution that occurs while the participant remains on the initial strategy, rather than resolution alone. This distinction matters: a participant whose course leads to a management change does not meet the endpoint as defined, even if the pregnancy ultimately resolves. The endpoint therefore reflects both clinical resolution and the course of management during follow-up.

For the posted results, the event counts are 31 of 86 participants in expectant management, 42 of 87 in uterine evacuation with methotrexate for some, and 45 of 82 in empiric methotrexate for all. The registry describes the primary outcome as uneventful clinical resolution without change in treatment from the initial strategy. It does not provide a more detailed operational definition of “uneventful,” or additional information about how a change in treatment was classified.

As a binary outcome, the measure can be compared using the difference between the event proportions in two arms. That contrast describes the observed frequency of meeting the defined endpoint; it does not describe every aspect of symptoms, safety, time to resolution, or subsequent care. Those broader outcomes are not established by this endpoint alone.

7. Results Posted in the Registry

• Uterine Evacuation With MTX for Some: 48.3% (42/87) versus 36.0% (31/86) on control; risk difference 12.2 percentage points (95% CI -2.4 to 26.8), risk ratio 1.34 (0.94–1.91); unadjusted two-proportion z-test p = 0.103.
• Empiric Treatment With MTX for All: 54.9% (45/82) versus 36.0% (31/86) on control; risk difference 18.8 percentage points (95% CI 4.0 to 33.6), risk ratio 1.52 (1.08–2.15); unadjusted two-proportion z-test p = 0.014.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: the registry reports the number of participants who had uneventful clinical resolution without a change from their initial management strategy. For a binary endpoint, an arm’s event proportion is the count meeting the endpoint divided by the number of participants in that arm. Comparing two such proportions can be expressed as a risk difference: the event proportion in one arm minus the event proportion in the reference arm. A positive risk difference means the event was more frequent in the first arm in the posted comparison.

What does the risk difference describe?

The posted risk differences compare each active strategy with expectant management. For uterine evacuation with methotrexate for some, the estimate is 0.122. For empiric methotrexate for all, it is 0.188. These are absolute contrasts on the proportion scale, rather than relative contrasts. They describe the observed difference in the probability of meeting this specific endpoint between the compared arms. They do not describe a difference in all forms of clinical resolution or in outcomes that were not posted.

Other relative measures appear in the posted comparison data, including risk ratios and odds ratios. A risk ratio compares the event proportions as a ratio, while an odds ratio compares the odds of the event. These measures answer related but distinct questions and can look different in magnitude because they use different scales. The primary interpretation emphasizes the risk difference because it describes the absolute contrast. The record does not report a model-based adjustment for participant characteristics.

How should a confidence interval be understood?

A confidence interval describes uncertainty around an estimated effect under the statistical method used to construct it. It is not a range that guarantees the true effect lies within its endpoints, nor does it indicate how many participants had the outcome. For the uterine-evacuation comparison, the 95% confidence interval for the risk difference runs from -0.024 to 0.268. For empiric methotrexate, it runs from 0.040 to 0.336. A confidence interval that includes zero is compatible with no risk difference under the conventional interpretation of this measure. An interval that excludes zero indicates that zero is not among the values retained by that interval procedure, but does not resolve questions about bias, clinical importance, or multiplicity.

The corresponding unadjusted p-values are 0.103 and 0.014. A p-value measures how incompatible the observed data are with a specified null model, given the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the probability that the result will replicate. Since the registry record does not report an adjustment for multiple comparisons, the values should not be treated as multiplicity-adjusted evidence.

Why does the endpoint definition matter?

“Clinical resolution without change from the initial management strategy” is a compound description of the course: the pregnancy of unknown location resolves, and management is not changed from the assigned starting strategy. As a result, the event count can depend both on resolution and on whether a change in management occurred. The record’s description does not provide further operational detail about what qualified as a change or as uneventful resolution. Comparisons therefore need to retain the exact endpoint wording rather than being paraphrased as resolution alone.

What does randomization contribute?

Random allocation is intended to make treatment groups comparable on average with respect to measured and unmeasured baseline factors, apart from chance. It supports an interpretation of between-arm contrasts as comparisons of assigned strategies, subject to the conduct of the trial, missing outcome data, and the analysis approach. Randomization does not remove uncertainty, guarantee balanced groups, or ensure that participants followed their initial strategy throughout follow-up. The record describes clinical treatment as indicated by disease progression, and the primary endpoint explicitly requires no change from the initial strategy.

The registry record identifies a randomized, parallel, unmasked phase 3 trial with three strategies. It does not report the detailed statistical plan, analysis population, missing-data method, or whether any covariate adjustment was prespecified. These omissions limit assessment of how the posted comparisons were selected and analyzed. No additional statistical assumptions about the trial’s original design should be inferred from the posted estimates.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate the contrast between management strategies. The primary-outcome risk-difference interval for uterine evacuation with methotrexate for some is -0.024 to 0.268. Its span includes zero and covers both a small negative contrast and positive contrasts. This means the observed data do not pin down the direction and size of this comparison with high precision.

For empiric methotrexate for all, the interval is 0.040 to 0.336. It lies above zero, but still covers a range of possible positive contrasts. The point estimate, 0.188, is only one estimate within that interval; it should not be treated as the exact underlying effect. The interval describes statistical uncertainty under the analysis method, not uncertainty from every possible source, such as outcome classification or missing data.

Both intervals are based on the posted comparisons with expectant management. They do not provide a confidence interval for a direct comparison between the two active strategies. Nor do they establish how the estimates would apply outside the enrolled population and follow-up timeframe. The registry record does not report further details needed to assess whether the interval calculations were adjusted for covariates, missing outcomes, or multiple comparisons.

Precision is different from statistical significance and from clinical importance. An interval excluding zero can still include effects of differing practical importance, while an interval including zero can remain compatible with potentially meaningful effects in either direction. The registry record does not provide a threshold for what difference would be clinically important. The estimates therefore support careful description of the observed contrasts and their uncertainty, rather than a definitive ranking of the strategies.

11. 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 sample-size planning illustrations are planning calculations, not observed trial results. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. The registry record does not report the trial’s own original sample-size assumptions or justification.

The displayed figures are participants per arm, not total participants across a comparison. The 80% power column gives the planned number per arm under the stated assumptions for a design with 80% power to detect the specified effect. The 90% power column gives the per-arm number for a design with 90% power under those assumptions. Power is a property of a proposed design under an assumed effect and statistical model; it is not a measure of how likely the observed result is to be true.

Rows planning for 100%, 75%, and 50% of the observed effect illustrate how the planning requirement changes as the assumed effect becomes smaller. Smaller effects require more participants per arm to attain the same target power, all else equal. The values differ between the two comparisons because the observed effects used for planning differ. These illustrations should not be read as evidence that the trial was designed using those assumptions, or as evidence about the power achieved in the completed trial.

This is not observed power. The calculations are conditional planning illustrations based on the observed effect and stated assumptions; they cannot replace the confidence intervals when assessing the precision of the trial results.

12. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.360; treatment proportion p₁ = 0.483; average p̄ = 0.422.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6984 = 1.3688.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6930 = 0.5832.
4. n = (1.3688 + 0.5832)² / (0.1223)² = 254.8, rounded up to 255 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
p0 <- 0.36046511627907                          # control proportion
p1 <- 0.482758620689655                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2152696)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 255 (80% power), 341 (90% power)
 75% of observed effect: n per arm = 449 (80% power), 601 (90% power)
 50% of observed effect: n per arm = 999 (80% power), 1,337 (90% power)
power.prop.test: 254.8 
Simulated power at n = 255 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record posts two primary-outcome comparisons, each contrasting an active strategy with expectant management. Their p-values are unadjusted: 0.103 for uterine evacuation with methotrexate for some and 0.014 for empiric methotrexate for all. The record does not report whether the study team prespecified a hierarchy, adjusted for multiple comparisons, or used another multiplicity strategy. The p-values should therefore be interpreted as nominal results for the individual comparisons, not as values known to control an overall error rate across a family of tests.

The record lists one outcome measure and no secondary outcomes posted. That does not establish that no other analyses were planned or conducted; those details are not reported in the registry record. It also does not provide a detailed statistical analysis plan, including any prespecified primary contrast, covariate adjustment, subgroup analysis, sensitivity analysis, or approach to model selection. The posted pairwise estimates can be described, but the record does not allow a full assessment of whether the reported comparisons were the only planned comparisons.

Missing-data handling is also not reported in the registry record. The posted arm counts give the participants included in the displayed primary-outcome results, but there is no description of whether all randomized participants had complete outcome information, how unavailable outcomes were handled, or whether an analysis population was defined in advance. There is no reported imputation method, sensitivity analysis for missing outcomes, or explanation of exclusions from analysis.

These gaps matter because missing outcomes and analytic choices can affect the interpretation of a randomized comparison. Randomization supports comparisons of assigned strategies, but analysis populations and incomplete follow-up may influence how closely posted results represent that randomized comparison. Without the relevant details, it is not possible to determine whether the estimates are intention-to-treat, per-protocol, or based on another population. The registry record does not report that classification, so none should be assumed.

14. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: salpingectomy (2.3%), hospitalization (1.1%), right ruptured ectopic pregnancy (1.1%).

The registry reports serious adverse events affecting 2 participants in expectant management, 2 in uterine evacuation with methotrexate for some, and 0 in empiric methotrexate for all. The corresponding numbers of participants at risk are 86, 87, and 82. The record reports no deaths in any arm. These are participant counts, not event rates, and they do not by themselves establish whether an event was caused by the assigned strategy.

The most frequently listed serious-event terms are salpingectomy at 2.3%, hospitalization at 1.1%, and right ruptured ectopic pregnancy at 1.1%. The registry lists these terms and percentages but does not provide further detail in the posted serious-event summary about timing, severity beyond the serious classification, or attribution. The percentages should be read as registry-reported values rather than recalculated estimates.

Other adverse events were reported for 44 participants in expectant management, 53 in uterine evacuation with methotrexate for some, and 46 in empiric methotrexate for all. These figures are separate from the serious-event counts and do not specify the number or nature of events per participant. Differences in these counts should not be interpreted as evidence of comparative safety without fuller definitions, follow-up details, and statistical analysis. The registry record does not report such an analysis.

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

The posted results describe how often participants met the trial’s defined primary endpoint under the three assigned management strategies. The event counts were 31 of 86 in expectant management, 42 of 87 in uterine evacuation with methotrexate for some, and 45 of 82 in empiric methotrexate for all. The endpoint required clinical resolution without changing from the initial management strategy within 6 weeks from randomization.

Against expectant management, the risk-difference estimate for uterine evacuation with methotrexate for some is 0.122, with an interval from -0.024 to 0.268. For empiric methotrexate for all, the estimate is 0.188, with an interval from 0.040 to 0.336. These results describe the comparisons and uncertainty in the posted data. The second interval excludes zero, while the first includes zero, but statistical interpretation also depends on the endpoint, analysis choices, and the fact that the p-values are unadjusted.

The findings do not establish that one strategy is best for every participant, nor do they show that the strategies have the same effects on outcomes that were not measured or posted. The registry record does not report a direct comparison of the two active strategies, longer-term outcomes, or subgroup estimates. It does not provide a clinical-importance threshold for the risk difference. Accordingly, the estimates alone cannot establish the practical importance of a contrast.

The endpoint is not synonymous with resolution under any care pathway: a change from the initial strategy means the endpoint is not met as defined. The posted event counts should not be interpreted as a complete accounting of all participants whose pregnancy ultimately resolved. Likewise, the adverse-event summary does not establish causation or a comprehensive comparative safety profile.

The results are specific to the studied population, management strategies, endpoint definition, and follow-up timeframe described in the registry. They do not determine what should be done in an individual clinical situation. A reader can use them to understand the observed endpoint frequencies and the uncertainty around the pairwise comparisons, while recognizing the limits of the record.

16. Why This Trial Matters Statistically

This trial raises statistical issues that are important when a clinical outcome depends on both disease course and management decisions. Its primary endpoint required clinical resolution without a change from the initial strategy. That definition makes the outcome clinically interpretable as a course completed on the starting approach, but it also means the event is not simply a measure of resolution. Understanding the endpoint is essential before comparing the arm counts.

The three strategies differ in more than a single treatment component. Expectant management involves hCG monitoring, uterine evacuation can be followed by methotrexate depending on hCG response, and empiric management includes methotrexate with additional doses as needed. The randomized contrasts therefore concern management strategies as packages. They cannot isolate the effect of methotrexate, evacuation, monitoring, or another component by itself.

The two posted pairwise comparisons have different levels of precision and different interval relationships to zero. Reporting estimates with confidence intervals, rather than relying only on p-values, shows both the direction and the range of effects compatible with the data under the calculation. The unadjusted p-values also make multiplicity a relevant interpretive concern, since the registry record does not report an adjustment plan.

The planning illustrations demonstrate how assumptions about the effect to be detected influence the participant requirements for a proposed study. They are not a substitute for the actual uncertainty in the completed trial, and they do not reveal the original design rationale. This distinction helps prevent observed results from being mistaken for prospective design assumptions.

Finally, the registry’s limits are statistically meaningful. Missing-data procedures, analysis populations, and a detailed analysis plan are not reported. These omissions restrict evaluation of how the posted estimates were obtained and how robust they may be to alternative decisions. Transparent estimates remain informative, but their interpretation should remain linked to the endpoint, comparison, uncertainty, and available reporting.

17. 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 registry record does not report detailed eligibility criteria, beyond describing hemodynamically stable women with confirmed PPUL in the trial summary. The results should therefore be read in the context of that summary rather than assumed to apply to populations with different clinical circumstances. The record does not describe the sites, participant characteristics, or baseline distributions, limiting assessment of how the enrolled population compares with other groups.

The primary endpoint has a specific definition and timeframe: uneventful clinical resolution without a change from the initial management strategy, assessed 6 weeks from randomization. The registry does not give further operational detail about “uneventful” resolution or classifying a change in management. The results do not show resolution regardless of strategy changes, nor do they establish outcomes after the stated timeframe.

The record lists no masking. It does not report how outcome assessment was conducted or whether outcome classification was independent of treatment assignment. The strategies themselves include different procedures, medication, and monitoring, and participants could be treated clinically as indicated by progression. These features make the strategy-level comparison relevant, but also mean the results cannot be attributed to a single treatment component.

Detailed methods for missing outcomes and analysis populations are not reported. Nor are the original sample-size justification, a full statistical analysis plan, or multiplicity handling. The posted estimates are therefore best read as registry results with these reporting limits, not as a complete account of every analytic decision. The record also does not report a direct comparison between the two active strategies or a threshold for clinical importance.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Optimal Treatment for Women With a Persisting Pregnancy of Unknown Location — NCT02152696.
• Registry record last updated 2020-12-08; status last verified 2020-11.
• Results first posted 2020-10-26.
• 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.

21. Record Summary

The registry describes a completed, randomized, parallel, unmasked phase 3 trial sponsored by Yale University, with enrollment of 255. Its recorded start date is 2014-07-25 and primary completion is listed as 2019-08. The trial compared expectant management, uterine evacuation with methotrexate for some, and empiric methotrexate for all among women with a persisting pregnancy of unknown location.

The primary outcome was uneventful clinical resolution without a change from the initial management strategy within 6 weeks from randomization. Posted counts were 31 of 86 for expectant management, 42 of 87 for uterine evacuation with methotrexate for some, and 45 of 82 for empiric methotrexate for all. Pairwise risk differences versus expectant management were 0.122 and 0.188, respectively, with confidence intervals and unadjusted p-values described in the statistical interpretation.

The registry record does not report a detailed analysis plan, missing-data methods, the original sample-size justification, or multiplicity handling. Safety counts are reported separately and do not establish causation.