Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma (NCT03787303), a na phase 2 study. The primary outcome is Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care.

2. Clinical Question

The study asked whether progression-free survival could be evaluated in people with metastatic breast carcinoma and hypothyroidism who were rendered euthyroid and hypothyroxinemic while receiving T3. The planned primary endpoint was the number of participants with progression-free survival at 12 months, assessed using clinical and radiological assessments completed as part of routine care. The registry record does not report the number meeting that endpoint or a progression-free survival estimate.

This is therefore a single-arm assessment rather than a direct comparison of T3 with another treatment or with a control group. Any interpretation concerns the recorded study experience and the endpoint as defined, not a comparative estimate of treatment effect.

3. Trial Design

The registry describes a single-arm phase II pilot study sponsored by Aultman Health Foundation. It lists no randomized allocation, no masking, and one intervention: the drug triiodothyronine (T3). Enrollment was 7. The study started on 2019-03-01, and the primary completion date was 2022-03-09. Its status is terminated.

The arm description says participants would discontinue L-thyroxine (T4) before starting T3 at a 3:1 ratio. The investigator would titrate the dose to maintain free T4 < 50% of the normal range while maintaining a euthyroid state. The description of the tablets is incomplete in the registry record, so further administration details are not reported in the registry record.

The primary outcome was the number of participants with progression-free survival at 12 months, based on clinical and radiological assessments performed as part of routine care. The registry defines progression using RECIST v1.1: a 20% increase in the nadir sum of the longest diameter of target lesions, unequivocal progression in existing non-target lesions, or the appearance of one or more new lesions.

The registry lists secondary outcomes concerning the number of screened patients with both metastatic breast cancer and hypothyroidism, quality of life measured with the FACT-B questionnaire, energy level measured with a FACT-B question, and time to achieve a euthyroid hypothyroxinemia state. It reports 5 outcome measures overall, but does not give results for those secondary outcomes in the record summarized by these registry entries. The reason for termination and the detailed statistical plan 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: All enrolled participants underwent a four day washout period of L-thyroxine (T4) prior to Triiodothyronine (T3) initiation. There were no enrolled participants who were excluded from the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Last enrolled subject was only able to be followed for 9 months due to early termination of study. Subject not included in primary outcome measure.

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 Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care, measured over 12 months.

The primary endpoint is a count: the number of participants with progression-free survival at 12 months. It is not reported as a hazard ratio or as a comparison between treatment groups. The endpoint uses a clinically recognizable event—disease progression assessed through routine clinical and radiological care—to describe whether participants remained free of documented progression over the specified follow-up period.

The registry defines progression using RECIST v1.1. The listed criteria include a 20% increase in the nadir sum of the longest diameter of target lesions, unequivocal progression in existing non-target lesions, or the appearance of one or more new lesions. The registry does not report how many participants met the progression-free survival endpoint.

In general, a fixed-time endpoint can make the question easy to state, but interpretation depends on whether participants have adequate follow-up to reach that time point and on how missing or incomplete assessments are handled. The registry notes that the last enrolled subject could be followed for only 9 months because of early study termination and was not included in the primary outcome measure. The approach to other incomplete follow-up or assessment data is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group phase II pilot study, rather than a randomized comparison. This design determines what statistical interpretations are possible: there is one treatment group and no concurrent control group identified in the record. The primary endpoint is a participant count at a defined follow-up time, while the listed secondary outcomes include both counts and measurements intended to be assessed over time. The record reports 5 outcome measures and 0 analyses.

What does a single-group design estimate?

In general, a single-group study can describe the outcomes observed among participants who received the intervention. It does not directly estimate a between-group contrast because there is no comparator group. A change over time, if reported, would describe the observed course in the study participants; without a comparison group, it would not isolate the intervention from other influences. Here, the registry does not report a primary endpoint result or results for the listed secondary outcomes.

The design lists allocation as not applicable and masking as none. These details mean the registry does not describe random assignment or masking. Random assignment is generally used to make treatment groups more comparable with respect to measured and unmeasured characteristics, while masking can reduce some influences on assessment or reporting. Neither feature supplies a comparison when a study has only one group. The record does not report additional procedures intended to address these design limitations.

How should a count endpoint be understood?

The primary measure is the number of participants with progression-free survival at 12 months. A count is a direct tally of participants meeting the endpoint definition. A proportion would put that count in relation to an analysis population, and a confidence interval would describe uncertainty around an estimate. The registry record does not report the endpoint count, analysis denominator, proportion, or confidence interval, so none should be inferred.

In general, a confidence interval is a range of values compatible with the data under a stated statistical method. It communicates uncertainty rather than guaranteeing that the true value lies within the range. With a small study population, estimates can be imprecise, but the precision of this study’s primary endpoint cannot be assessed from the registry record because the result and analysis population are not reported.

The endpoint uses a 12-month time point. In general, time-to-event methods can use information from participants followed for different lengths of time, provided the methods and assumptions are specified. The registry’s primary outcome is instead described as a count at 12 months, and the outcome population note says that the last enrolled subject had only 9 months of follow-up and was not included. The record does not report a time-to-event analysis or a method for handling incomplete follow-up.

What role does the progression definition play?

The registry defines progression using RECIST v1.1 criteria: a 20% increase in the nadir sum of the longest diameter of target lesions, unequivocal progression in existing non-target lesions, or one or more new lesions. Such operational criteria make an endpoint more reproducible by specifying what qualifies as progression. In general, consistency in measurement and assessment is important because differences in timing or interpretation can affect whether an event is recorded. The record says assessments were completed as part of routine care, but does not report detailed assessment schedules, independent review procedures, or missing-assessment rules.

What do the planning assumptions mean?

The stated sample-size assumptions describe planning illustrations based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These are assumptions for hypothetical planning exercises, not a description of the single-group trial’s design. The registry does not report the trial’s own sample-size justification, and the stated two-arm allocation assumption does not match the listed single-group design. Such illustrations should not be read as observed power or as evidence that the trial was designed or conducted with a comparator arm.

In general, sample-size planning asks how much information a future study would need to evaluate a specified effect under chosen assumptions. A planning calculation is not a measure of the probability that the observed study result is correct. Nor can a planning result substitute for a reported endpoint estimate and its uncertainty. The registry record does not report an effect estimate for the primary endpoint, so the posted information does not support numerical interpretation of the planning illustrations.

Why can over-dispersion matter?

In general, over-dispersion means that observed variation is greater than expected under a statistical model’s assumptions. It can make standard errors too small if the model does not account for that extra variation, leading to confidence intervals that are too narrow and tests that may be too optimistic. Whether over-dispersion is relevant depends on the outcome and model. The registry record reports no analyses, so it does not identify a fitted model or report an assessment of over-dispersion. It would not be appropriate to claim that a particular model or correction was used.

More broadly, the statistical plan, any interim analyses, and any model-specific assumptions are not reported in the registry record. The posted design and outcome descriptions allow the endpoint and its limitations to be explained, but they do not disclose enough information to reconstruct an analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Triiodothyronine (T3)")
n      <- c(6)
events <- c(4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Triiodothyronine (T3)  6  4  66.7  22.3  95.7  30.0  90.3  29.0  90.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including the primary progression-free survival count and secondary measures concerning screening, quality of life, energy level, and time to achieve the thyroid state. It reports 0 analyses. The registry record does not describe a multiplicity adjustment or a testing hierarchy. In general, evaluating several outcomes can increase the chance of at least one apparently notable result if each is tested separately; a prespecified strategy can clarify which comparisons are confirmatory and how results should be interpreted. No such strategy is reported in the registry record.

Missing-data handling is also not reported. The primary-outcome note states that the last enrolled subject could be followed for only 9 months because of early termination and was not included in the primary outcome measure. The note does not identify the analysis denominator or explain how the remaining outcome data were handled. It does not say whether participants with incomplete clinical or radiological assessments were excluded, censored, or handled by another approach.

The registry record does not report analysis populations, such as whether the endpoint was analyzed among all enrolled participants or a defined subset. It also does not report imputation, sensitivity analyses, or an interim-analysis plan. These are absences of reporting, not evidence that a particular procedure was or was not undertaken outside the record. Because the primary count and its denominator are unavailable, the effect of the excluded subject on the reported endpoint cannot be quantified.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pleural effusion (14.3%), cellulitis (14.3%), ascites (14.3%).

For the T3 group, the registry lists 7 participants at risk for serious adverse events and 2 participants affected. It lists 7 at risk for other adverse events and 7 affected, and reports 1 death. These are participant counts in the registry’s safety record. They are not estimates of comparative risk because the study has no separate control group.

The serious adverse event terms listed are pleural effusion, cellulitis, and ascites, each reported as 14.3%. The record does not say whether these terms occurred in distinct participants or whether a participant could contribute more than one term. It also does not establish whether any listed event or the death was related to T3. The counts should therefore be read descriptively, without assigning causation.

In general, adverse-event counts depend on how events are defined, collected, and coded. The registry record does not provide details about event timing, duration, severity beyond the serious-event classification, or individual-level overlap. The reported safety figures describe events recorded for this group; they do not establish a comparative safety profile.

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

The study record documents a phase II pilot investigation of T3 in a single group of participants with metastatic breast carcinoma and hypothyroidism. It describes a target thyroid state, a 12-month progression-free survival endpoint, and criteria for defining progression. It also records enrollment of 7 and notes that the study was terminated before the last enrolled subject could complete 12 months of follow-up.

What the record does not provide is the primary endpoint count, an estimate of progression-free survival, or the denominator used for that endpoint. It also does not report results for the listed secondary outcomes. Without those results, the registry cannot show how participants’ disease status, quality of life, energy level, or time to reach the specified thyroid state changed during the study.

The single-group design also limits what any reported outcome could establish. In general, outcomes observed in a treatment group do not by themselves show what would have happened to comparable participants under another approach. There is no randomized or otherwise described comparator in this record, and the listed design has no masking. The registry therefore does not provide a direct comparative estimate.

The safety counts are likewise descriptive. They identify serious adverse events in 2 participants and other adverse events in 7 participants, with 1 death recorded. The relationship of those events to treatment is not reported, and the record does not describe a comparative safety assessment. The counts should not be interpreted as proof of either causation or absence of causation.

In general, a pilot study can describe feasibility and generate questions for further evaluation, but its interpretation depends on the outcomes actually reported and on the design. The registry record does not state the study’s sample-size justification or its detailed statistical plan. Taken together, the posted information supports a limited account of design, follow-up, and safety reporting, but does not support a conclusion about the primary endpoint result or whether T3 changed progression-free survival.

14. Why This Trial Matters Statistically

This study is statistically notable because its primary question is framed as a fixed-time outcome in a single-group pilot, while the record also documents an early-termination follow-up limitation. Those features make the analysis population and completeness of follow-up central to interpretation. The registry explicitly says that the last enrolled subject had only 9 months of follow-up and was excluded from the 12-month primary outcome measure, but does not report the resulting denominator or endpoint count.

The distinction between a planned endpoint and a reported result is important. A detailed progression definition does not substitute for the outcome data themselves. The registry specifies RECIST v1.1 progression criteria, but without a participant count or estimate it is not possible to describe the observed primary endpoint or its precision.

The study also illustrates why design and planning assumptions should be considered separately. The registry describes a single group with no allocation and no masking, while the stated sample-size assumptions refer to equal allocation between two arms and a normal approximation. Those planning assumptions do not turn the study into a comparative trial and should not be read as evidence of observed power.

Finally, the record lists several secondary outcomes and safety counts but reports no analyses. This underscores the value of complete outcome reporting: readers need the results, analysis populations, uncertainty estimates, and handling of incomplete data to understand what the study can establish. Where those details are absent, a restrained interpretation is more informative than an unsupported estimate.

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.

Enrollment was 7, and the study is described as a single-group phase II pilot. With no separate comparator, the design cannot provide a direct treatment-group contrast. The registry reports no masking, and it does not describe independent or blinded endpoint review. These features limit causal interpretation of any outcomes that might otherwise have been reported.

The primary endpoint is defined at 12 months, but the record says the last enrolled subject could be followed for only 9 months because of early termination and was excluded from the primary outcome measure. The reason for termination is not reported in the registry record. Neither the number included in the endpoint analysis nor the primary endpoint result is reported, and the handling of other incomplete follow-up is not described.

The primary assessment was based on clinical and radiological assessments completed as part of routine care. The registry supplies progression criteria but does not report detailed assessment timing, data completeness, or any independent review procedure. The detailed statistical plan, sample-size justification, interim analyses, and analysis populations are not reported in the registry record.

The arm description is incomplete after its statement about oral T3 tablets. The registry record also lists secondary outcome topics without reporting their results. Safety counts are available, but event timing, individual overlap, and relationship to treatment are not stated. These limitations mean the record gives useful design and descriptive information, but not enough detail to assess the primary endpoint estimate, its precision, or a comparative treatment effect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma — NCT03787303.
• Registry record last updated 2022-05-13; status last verified 2022-05.
• Results first posted 2022-05-13.
• 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

NCT03787303 is listed as a terminated, single-arm phase II pilot study sponsored by Aultman Health Foundation. It enrolled 7 participants and evaluated triiodothyronine (T3) in metastatic breast carcinoma with hypothyroidism. The primary endpoint was the number of participants with progression-free survival at 12 months, assessed through routine clinical and radiological care and defined using RECIST v1.1 progression criteria.

The registry says the last enrolled subject could be followed for only 9 months because of early termination and was excluded from the primary outcome measure. It does not report the primary endpoint result, secondary outcome results, the analysis population, or a detailed statistical plan. Safety records list 2 participants with serious adverse events, 7 with other adverse events, and 1 death; treatment relationships are not reported. The record supports descriptive interpretation of design and reporting, not a comparative treatment-effect conclusion.