Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients (NCT02910219), a randomized phase 2 study. The primary outcome is Diarrhea for >= 2 Consecutive Days.

2. Clinical Question

The question is whether adding crofelemer during the first chemotherapy cycles is associated with the occurrence of sustained diarrhea, as defined by the endpoint. The registry record describes the planned comparison, but not an outcome estimate. It therefore supports describing what the trial set out to assess, rather than drawing a conclusion about whether diarrhea was less frequent in either group.

3. Trial Design

HALT-D is described as a phase 2, randomized, parallel-group study. Enrollment was 53. The masking status is listed as none, so the record describes the trial as unmasked. The registry lists Breast Cancer as the condition and crofelemer as the study drug. The sponsor is listed as Sandra Swain.

The crofelemer group took one 125 mg tablet twice a day during cycles 1–2 of chemotherapy with THP or TCHP. The treatment description says participants were monitored off crofelemer during cycle 3. The control group was followed for cycles 1–3 and did not receive crofelemer at any time in the study. The official title identifies the chemotherapy components as trastuzumab, pertuzumab, and docetaxel or paclitaxel, with or without carboplatin. Each cycle is described as 21 days for the primary outcome timeframe.

The primary outcome concerns diarrhea lasting 2 or more consecutive days during cycles 1 and 2. Secondary outcomes listed in the record include any-grade and Grade 3–4 diarrhea, onset and duration of diarrhea, duration of Grade 3–4 diarrhea, use of anti-diarrheal medications, and FACIT-D scores.

The study is marked completed. Its recorded start date is 2017-01-31, and its primary completion date is 2020-11-23. The registry record does not report the randomization procedure, allocation concealment, detailed eligibility criteria, or a full statistical analysis plan. Those details cannot be inferred from the design labels alone.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

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 Diarrhea for >= 2 Consecutive Days, measured over Cycle 1, Cycle 2 (each cycle is 21 days).

The primary endpoint is the percentage of participants who experienced any-grade diarrhea lasting 2 or more consecutive days during cycles 1 and 2 of chemotherapy. The grading reference is CTCAE 4.0. This endpoint focuses on duration as well as occurrence: a participant must have diarrhea meeting the duration definition, rather than merely any recorded episode of diarrhea.

A percentage is a binary-outcome summary: each participant is classified according to whether the endpoint definition was met, and the group result describes the proportion meeting it. Such an endpoint can be useful when the clinical question concerns how commonly a specified event occurs during a defined period. The duration threshold also distinguishes sustained episodes from shorter events, while the any-grade definition includes diarrhea across severity grades.

The outcome is specified for both Cycle 1 and Cycle 2, each described as 21 days. The registry record indicates that the primary outcome has several categories or time points and is not reduced to one comparison. It does not report the percentages by group, a treatment-effect estimate, or uncertainty around an estimate. As a result, the endpoint definition can be explained, but the observed frequency and any between-group contrast cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main statistical distinction is between an endpoint definition and an endpoint result. The definition says what will count as an event: any-grade diarrhea lasting 2 or more consecutive days during the specified chemotherapy cycles. A result would additionally report how many participants met that definition in each group and an estimate of the contrast between groups. The registry record gives the definition but does not report those outcome results.

What a percentage describes

For a binary endpoint, each participant is classified as meeting or not meeting the event definition. The percentage describes the share of assessed participants who met it. It is important to know the denominator as well as the percentage: a percentage based on a different number of evaluable participants can have different precision. The registry record gives overall enrollment but does not report the endpoint denominators by group or cycle.

The outcome is duration-based. A participant with an episode shorter than the stated threshold would not meet this particular endpoint definition, although that episode could be captured by another diarrhea outcome. This is one reason the listed secondary outcomes—including diarrhea of any grade and diarrhea duration—address related but distinct questions.

Comparisons and uncertainty

A comparison between randomized groups would commonly be expressed as an effect estimate with a confidence interval. In general, a confidence interval describes a range of values compatible with the data and the method used, and it conveys precision as well as direction. A narrow interval indicates greater precision than a wide interval, all else equal. The registry record reports no confidence interval or primary-outcome estimate, so neither direction nor precision can be assessed.

A p-value, in general, describes how surprising the observed data would be under a specified null model and assumptions. It is not a measure of the size or clinical importance of an effect. No primary-outcome p-value is reported in the registry record. The absence of a reported p-value is not itself a test result and cannot be read as evidence for or against a difference.

Repeated time points and multiplicity

The primary endpoint concerns Cycle 1 and Cycle 2, and the registry also lists multiple secondary outcomes. When several outcomes or time points are examined, the chance of a misleading nominal finding can increase if each is tested independently without a plan for multiplicity. Statistical approaches may define one primary contrast, adjust for multiple comparisons, or treat analyses as exploratory. Which approach was intended for HALT-D is not reported in the registry record.

The trial is described as randomized and parallel-group. Randomization is intended, in general, to support comparable groups at the start of a study, subject to the actual allocation process and chance variation. The record does not describe the sequence-generation method or allocation concealment. With no masking reported, knowledge of treatment assignment could potentially affect some aspects of outcome recording or care; the registry does not describe safeguards or assess whether this occurred.

Sample size and power

In general, a sample-size plan depends on assumptions about the expected event frequency, the effect the study is designed to detect, the significance level, and the desired power. A planning calculation does not establish the effect observed in a trial. Nor does a sample-size calculation based on an observed effect represent observed power. The registry record does not report the trial’s own sample-size justification or the assumptions underlying its enrollment target.

The record describes an illustrative planning framework based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It states that such planning values are illustrations, not the trial’s own design rationale. However, the registry record does not provide a primary-outcome result from which to assess an effect estimate or its uncertainty. These planning assumptions cannot fill that gap or establish a trial finding.

Over-dispersion and model choice

For outcomes measured as counts, over-dispersion means that variability exceeds what a chosen model expects. In general, accounting for over-dispersion can prevent uncertainty from being understated when the model otherwise assumes less variability than the data show. The primary endpoint is defined as a percentage of participants meeting a binary criterion, not as a count rate. The registry record does not identify a statistical model, and it does not report enough outcome data to assess model fit or variability.

Overall, the available methods information is sufficient to describe the endpoint and broad trial structure, but not to reconstruct the analysis. The statistical analysis plan, model, covariate handling, confidence intervals, and treatment-effect results are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint definition and several secondary outcomes, including diarrhea frequency and severity, onset, duration, anti-diarrheal medication use, and FACIT-D scores. The primary outcome is described across Cycle 1 and Cycle 2, and the registry notes that it has several categories or time points rather than one reduced comparison. The record does not explain how these time points were combined or compared.

When multiple outcomes or time points are analyzed, multiplicity can make isolated nominal findings harder to interpret. A prespecified strategy may control the overall error rate, prioritize a particular contrast, or distinguish confirmatory analyses from exploratory ones. The multiplicity strategy is not reported in the registry record. The number and ordering of any planned hypothesis tests are also not reported.

Missing-data handling and analysis populations are not reported in the registry record. The enrollment of 53 does not establish how many participants had endpoint data, whether all randomized participants were included in each analysis, or how withdrawals or incomplete cycles were handled. The registry record also does not report imputation methods, sensitivity analyses, or reasons for missing observations.

These omissions limit interpretation: the endpoint definition is clear enough to describe, but the analysis denominator, treatment of incomplete data, and inferential framework cannot be evaluated. The record lists zero statistical analyses, so it does not provide outcome estimates or adjusted comparisons to resolve these uncertainties.

11. 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: neutrophil count decreased (4.0%), infections and infestations - other, specify (4.0%), obstruction gastric (4.0%), hyperglycemia (4.0%), dehydration (4.0%).

The posted serious adverse event summary gives the number at risk and the number affected in each group. In the crofelemer group, 1 of 26 participants at risk had a serious adverse event; in the control group, 7 of 25 participants at risk had a serious adverse event. The number of deaths was 0 in each group. These are descriptive counts from the registry record, not a reported statistical comparison.

The serious terms listed include Neutrophil count decreased, Infections and infestations - Other, specify, Obstruction gastric, Hyperglycemia, Dehydration, and Hyperkalemia, each reported as 4.0%. The registry record does not give further context for these term-level percentages, such as event timing, recurrence, or attribution. The figures should therefore be read as the posted safety summary, not as evidence that a particular event was caused by either study assignment.

Safety counts are not the primary diarrhea endpoint, and they do not establish the comparative effect of crofelemer on diarrhea. The registry record does not report statistical uncertainty or an adjusted analysis for the serious adverse event counts. Small group counts can be imprecise; general interpretation should account for the limited information in the record rather than treat the counts as definitive evidence of a safety difference.

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

The record describes a phase 2 randomized study designed to assess diarrhea during chemotherapy with and without crofelemer. It specifies the intervention schedule, comparator, primary endpoint definition, and a set of secondary outcomes. It also reports serious adverse event counts by group. These details make the study question and broad design understandable.

The record does not report the primary endpoint percentages, a treatment-effect estimate, a confidence interval, or a p-value. It therefore does not show whether the groups differed in diarrhea lasting 2 or more consecutive days, how large any difference was, or how precisely it was estimated. The absence of a reported result is not equivalent to a result showing no difference.

The safety summary describes events recorded in the groups, but it does not provide a statistical comparison or detailed context about event timing and attribution. It should not be used to infer a causal explanation for the observed counts. Likewise, the enrollment total is not a substitute for the number of participants contributing endpoint data.

More generally, statistical significance and clinical importance are different ideas. A statistical test, if reported, would address compatibility with a null model under its assumptions; an effect estimate and its uncertainty would be needed to judge the size and precision of a contrast. Neither is available for the primary outcome in the registry record. No medical conclusion about treatment should be drawn from a design description or from missing outcome results.

The appropriate interpretation is consequently limited: the registry record documents what HALT-D set out to study and some safety counts, but does not report enough efficacy analysis to answer the primary comparative question.

13. Why This Trial Matters Statistically

This study illustrates why a clearly specified clinical question and a reported clinical result are separate parts of trial interpretation. HALT-D identifies a defined population and treatment context, compares crofelemer with a control condition, and defines a duration-based diarrhea endpoint over specified chemotherapy cycles. Those design features explain what investigators intended to assess.

At the same time, a registry description is not a substitute for a reported analysis. The record gives enrollment and endpoint details but no primary outcome estimate or statistical analysis. Without group denominators, percentages, and a measure of uncertainty, readers cannot assess the magnitude or precision of the contrast. This distinction is important whenever a trial record contains a detailed protocol description but limited posted results.

The multiple secondary outcomes also highlight a common statistical issue. Different measures can capture different aspects of the same clinical experience, but assessing many outcomes and time points raises questions about prespecification and multiplicity. The registry record does not report the analysis strategy used to address those questions. That missing information limits the ability to distinguish primary inference from exploratory findings.

Finally, the safety counts illustrate the importance of reading denominators and event definitions alongside counts. Serious adverse event numbers offer descriptive information, while their interpretation depends on context, completeness, and uncertainty. The registry record does not report a comparative safety analysis. Taken together, these features make HALT-D useful for teaching the boundary between what a study design establishes and what only posted outcome analyses can establish.

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.

A central limitation of the registry record is that it does not report results for the primary endpoint. It gives neither the number nor the percentage of participants meeting the definition by group, and it supplies no effect estimate, confidence interval, or p-value. The primary outcome also spans Cycle 1 and Cycle 2, but the record does not state how those time points were analyzed.

The registry reports enrollment of 53, but does not report endpoint-specific denominators, participant flow, or the number of participants with complete data. Missing-data methods, analysis populations, and sensitivity analyses are not reported in the registry record. These omissions prevent assessment of whether the analyzed participants represented all randomized participants or whether incomplete observations could affect interpretation.

The trial is listed as randomized and unmasked, but the randomization procedure, allocation concealment, and methods for limiting bias in outcome assessment are not reported. The statistical analysis plan, sample-size justification, and approach to multiple outcomes are also not reported in the registry record. These details cannot be inferred from the phase or design labels.

The serious adverse event summary is descriptive and lacks a reported comparative analysis, event-level context, and information about attribution. The record also does not provide a primary efficacy result alongside the safety counts. As a result, the available safety information cannot fill the gaps in the primary-outcome reporting.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Diarrhea Prevention and Prophylaxis With Crofelemer in HER2 Positive Breast Cancer Patients — NCT02910219.
• Registry record last updated 2022-10-24; status last verified 2022-10.
• Results first posted 2022-10-24.
• 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

HALT-D, registered as NCT02910219, is a completed phase 2 randomized parallel-group study of crofelemer in HER2-positive breast cancer patients receiving chemotherapy with trastuzumab, pertuzumab, and docetaxel or paclitaxel, with or without carboplatin. Enrollment was 53, and masking is listed as none.

The crofelemer group took 125 mg twice a day during cycles 1–2 and was monitored off treatment during cycle 3. The control group received no crofelemer. The primary endpoint was any-grade diarrhea lasting 2 or more consecutive days during cycles 1 and 2, each described as 21 days.

The registry record does not report a primary-outcome result or statistical analyses. It reports serious adverse events in 1 of 26 participants at risk in the crofelemer group and 7 of 25 in the control group, with 0 deaths in each group. The study start date was 2017-01-31, and the primary completion date was 2020-11-23.