Treatment of Refractory Nausea and Vomiting in Patients With Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Refractory Nausea and Vomiting in Patients With Breast Cancer (NCT03367572), a randomized phase 3 study. The primary outcome is Average Nausea Defined as the Average [ MAXIMUM ] Nausea Rating Across 15 Assessment Points at Cycle 1 and 16 Assessment Points at Cycle 2 (Comparing Prochlorperazine or Olanzapine to Control Arm).

2. Clinical Question

The primary measure is an average of maximum nausea ratings across multiple daily assessment points. The scale runs from 1, not at all nauseated, to 7, extremely nauseated; higher scores indicate a worse outcome. The registry describes separate assessment schedules for the two chemotherapy cycles and frames the comparison as the added-drug groups versus control.

This question concerns reported nausea during treatment cycles, not only whether a participant experienced vomiting. The registry also lists secondary outcomes concerning maximum nausea on a 7-point scale and vomiting at Cycle 2 among participants who experienced chemotherapy-induced nausea and vomiting at Cycle 1. The record does not report the numerical primary comparison, so the direction, magnitude, and precision of any group differences cannot be described from the registry record.

3. Trial Design

This is a completed, randomized, double-masked, parallel-group phase III trial. The registry lists enrollment of 1363 participants and identifies breast carcinoma as the condition. The sponsor is the University of Rochester NCORP Research Base. The recorded start date is 2018-04-19, and the primary completion date is 2024-04-13.

Participants were assigned to one of three groups. Group I received netupitant/palonosetron hydrochloride on Day 1 and dexamethasone on Days 1–4, with placebo scheduled alongside chemotherapy. Group II received the same netupitant/palonosetron hydrochloride and dexamethasone regimen, with prochlorperazine and placebo. Group III received that common regimen, with olanzapine and placebo. The record gives more detailed timing and administration instructions for the groups, including oral dosing and scheduled doses around chemotherapy.

A parallel-group design assigns participants to a regimen and compares outcomes across groups rather than having each participant receive every regimen in sequence. Randomization is intended, in general, to support comparable groups on average at the time of assignment; it does not guarantee identical groups. Double masking indicates that the registry records the trial as double-masked, but it does not specify who was masked or describe procedures for maintaining masking.

The total enrollment does not establish how many participants were assigned to each group, completed each cycle, or contributed data to the primary analysis. Those group-specific primary-analysis counts and the allocation procedure are not reported in the registry record. The record lists 8 outcome measures and 7 analyses, but does not provide a complete account of how every outcome was analyzed.

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: 1363 subjects were enrolled. CYCLE 1 which is the First Chemotherapy Cycle (excluded 796 \[5 registration errors, 41 no four-day home record, 750 did not have average score of 3 or better\]) CYCLE 2 which is the Second Chemotherapy Cycle (excluded 250 \[subject decided not to continue on cycle 2\]). 317 subjects are available for randomization. 310 subjects were actually randomized.

Total Subjects Randomized

Second Chemotherapy Cycle (Cycle 2)

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 Average Nausea Defined as the Average [ MAXIMUM ] Nausea Rating Across 15 Assessment Points at Cycle 1 and 16 Assessment Points at Cycle 2 (Comparing Prochlorperazine or Olanzapine to Control Arm), measured over Nausea measured at Cycle 1 Chemotherapy (15 time points which is Days 1,2,3,4) and also measured at Cycle 2 Chemotherapy (16 time points which is Days 1,2,3,4).

The primary endpoint is average nausea, defined as the average of maximum nausea ratings across repeated assessment points at Cycle 1 and Cycle 2. Ratings use a 7-point scale: 1 means not at all nauseated, 4 means moderately nauseated, and 7 means extremely nauseated. Higher scores represent worse nausea. The registry describes 15 assessment points at Cycle 1 and 16 at Cycle 2, distributed across Days 1–4; the timing differs between the cycles as detailed in the record.

Using repeated ratings can describe nausea over more of a chemotherapy cycle than a single assessment could. Averaging them produces a continuous summary that can be compared between groups. That summary also compresses a pattern of ratings into one measure: it does not, by itself, show when nausea occurred, whether ratings changed over time, or how many participants had a particular experience. Those questions would require additional results.

The registry identifies the endpoint as a mean and its dispersion as a standard error. However, it does not report a single numerical primary comparison in the information available for this analysis. Group means, standard errors, a contrast estimate, and its confidence interval or p-value are therefore not reported in the registry record. The endpoint definition alone cannot establish the size or precision of a difference between groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies average nausea as a continuous outcome summarized by a mean, with standard error as the stated measure of dispersion. A mean describes the central value of a set of numerical observations. A standard error describes the estimated uncertainty of a statistic such as a mean; it is not the spread of individual participants’ nausea ratings. These are general statistical distinctions. The registry record does not provide the numerical primary means or standard errors needed to assess the actual data.

What does averaging repeated ratings represent?

The primary measure averages maximum nausea ratings collected at multiple assessment points in each of two chemotherapy cycles. Repeated assessments can capture experience across several days rather than relying on a single rating. The average provides a compact summary for a group comparison, but it can conceal differences in timing or variability among participants. Two groups could, in principle, have similar averages while having different patterns across assessment points; whether that occurred in this trial is not reported in the registry record.

The outcome definition gives 15 assessment points at Cycle 1 and 16 at Cycle 2. The record specifies the daily schedule for those assessments. It does not state how incomplete assessment schedules were handled, whether an average required a minimum number of completed ratings, or how the two cycles were combined or presented in the primary analysis. The endpoint title describes averages across Cycle 1 and Cycle 2, but a complete statistical specification for that combined outcome is not reported.

How should comparisons between groups be read?

A group comparison should be tied to a clearly defined contrast. In this trial, the stated primary comparison is between each experimental arm and the control arm. For a continuous outcome, an estimate of a difference in means would describe the contrast in scale units, with the sign depending on the subtraction order. Since higher nausea ratings indicate a worse outcome, interpretation would also need the direction of the contrast and the group labels. The registry does not report a single numerical contrast for the primary endpoint, so no group difference or direction can be stated.

In general, confidence intervals communicate uncertainty around an estimated effect, while standard errors can be used in inferential calculations under an analysis model. A confidence interval is not a guarantee that the true effect lies within its limits; it is interpreted through the statistical procedure and its assumptions. The primary outcome record names standard error but does not report numerical estimates or confidence intervals for a primary comparison. The model used to account for repeated ratings, if any, is not reported in the registry record.

What do the planning assumptions mean?

The sample-size material uses a planning illustration computed from the observed effect, rather than documenting the trial’s original design calculation. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. These assumptions describe the illustration; they do not establish that the trial was originally planned with those choices or that the illustration represents the trial’s actual power.

In general, a planning sample size estimates how many participants or events might be needed under specified assumptions. Such a calculation depends on the target effect, variability, significance level, allocation, and analysis method. When based on an observed effect, the illustration is not observed power and should not be read as proof that the trial was adequately or inadequately designed. The trial’s own sample-size justification is not reported in the registry record. No numerical planning values are interpreted in this discussion.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion occurs when observed variability exceeds what a model assumes. It can make standard errors too small if the model does not account for the additional variability, leading to overconfident inference. This is particularly relevant to some count outcomes, but the primary outcome is described as a continuous mean. The registry does not report a model or diagnostics that would allow a conclusion about over-dispersion or model fit for any analysis.

The record lists 7 analyses, but does not provide a complete account of their models, contrast definitions, covariate adjustments, assumptions, or diagnostic procedures. Accordingly, the primary outcome definition and general statistical concepts can be explained, but the actual estimation procedure and its assumptions cannot be independently assessed from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary nausea outcome, secondary nausea and vomiting outcomes, three treatment groups, multiple assessment points, and 7 analyses. When several outcomes, time points, or group comparisons are examined, multiplicity is a general statistical concern: the chance of at least one apparently notable result can rise as the number of statistical tests increases. Methods such as prespecifying a primary contrast or adjusting inference can address this concern, but the registry record does not report a multiplicity strategy, a hierarchy of comparisons, or which results were treated as confirmatory.

The primary outcome is described across Cycle 1 and Cycle 2 and includes repeated assessments within each cycle. The record does not report whether cycle-specific comparisons were planned, how the repeated observations entered the analysis, or whether any adjustment was made for multiple comparisons. The outcome description also notes that the primary outcome has several categories or time points and is not reduced to one comparison in the posted result. That limits interpretation of a single overall claim about the primary endpoint.

Methods for missing data are not reported in the registry record. The record does not state how missed nausea assessments, incomplete cycles, withdrawals, or other unavailable outcome measurements were handled. It also does not identify the primary efficacy analysis population, such as whether analyses followed original randomized assignment or required particular outcome data. Group-specific analysis counts and reasons for missingness are not reported.

These omissions do not establish that the trial lacked a prespecified plan or that missing data were mishandled. They mean that the registry record does not allow readers to evaluate those aspects of the analysis. The listed 7 analyses indicate that analyses are recorded, but without their definitions they do not resolve the questions about multiplicity, missingness, or analysis populations.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fatigue (1.8%), dizziness (1.1%), nausea (1.1%), anorexia (0.9%), mucositis oral (0.9%).

The registry reports adverse-event counts for three groups, with separate denominators for participants at risk of serious and other adverse events. For Group I, 1 of 91 participants was reported with a serious adverse event and 10 of 91 with other adverse events. For Group II, the corresponding counts are 3 of 110 and 19 of 110. For Group III, they are 3 of 109 and 14 of 109. The registry reports 0 deaths in each group.

These are counts within the listed adverse-event groups, not the total enrollment of 1363. The record does not explain in this summary why these denominators differ from total enrollment or provide the full safety analysis population. The numbers should therefore be interpreted with their stated denominators, not as counts from all enrolled participants.

The registry also lists serious adverse-event terms with percentages: fatigue, 1.8%; dizziness, 1.1%; nausea, 1.1%; anorexia, 0.9%; mucositis oral, 0.9%; and headache, 0.9%. These terms are not assigned to specific treatment groups in the listed information. The record does not provide enough detail to determine event duration, severity grading, relatedness assessments, or whether individuals experienced more than one event. Counts and listed terms describe reported safety information; on their own, they do not establish a causal comparison between regimens.

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

The registry record establishes that a completed randomized phase III trial compared three regimens in patients with breast cancer receiving chemotherapy. It defines average nausea across repeated assessments in two chemotherapy cycles as the primary outcome and identifies higher scale scores as worse nausea. It also lists secondary outcomes concerning maximum nausea and vomiting at Cycle 2 among participants with chemotherapy-induced nausea and vomiting at Cycle 1.

Those design and measurement details clarify the question the trial set out to address. They do not provide the numerical answer. No single primary comparison result, including a group estimate, contrast, confidence interval, or p-value, is reported in the registry record. Secondary outcome results are also not reported in the information available for interpretation. It is therefore not possible to describe the size, direction, or precision of an outcome difference from these registry entries.

In general, statistical evidence and clinical importance are related but distinct considerations. An estimate’s precision describes uncertainty, while a judgment about importance requires context and an appropriate interpretation of the outcome. The registry does not report a threshold for a meaningful change on the nausea scale, and no primary effect estimate is available to compare with such a threshold.

The posted safety counts document adverse events among the stated group denominators and report no deaths in the listed groups. They do not alone show that one regimen has a different safety profile from another. A comparative safety interpretation would require complete denominators, appropriate estimates and uncertainty, event definitions, and analysis context.

In short, the record supports a description of trial design, treatment groups, outcome definitions, and selected safety counts. It does not support a conclusion about whether the experimental regimens changed nausea or vomiting outcomes relative to control. A completed trial status or a planning illustration cannot replace reported outcome estimates.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that matter when interpreting clinical comparisons. First, nausea is assessed repeatedly within each chemotherapy cycle, while the primary endpoint is an average. Repeated measurements can represent experience over time, but the method used to account for their dependence affects uncertainty and inference. The registry describes the schedule and summary measure, but the analysis model for the repeated observations is not reported.

Second, the comparison has three groups and a primary outcome description spanning two cycles, alongside secondary outcomes. The inferential meaning of any result depends on which contrasts were prespecified and how multiple comparisons were addressed. The registry does not report a multiplicity plan or reduce the primary outcome to a single comparison result. This makes it especially important not to infer a treatment effect from the design description alone.

Third, a continuous scale average is a useful compact outcome, but averaging can hide variation across assessment times and participants. A mean and standard error, if reported with a well-defined contrast, would help describe central tendency and precision. The registry names these summary measures but does not report numerical primary estimates for interpretation.

Finally, enrollment, analysis population, and outcome-specific denominators are not interchangeable. The record lists enrollment of 1363, while the adverse-event groups have their own at-risk denominators. Primary outcome analysis counts are not reported. The planning illustration is also distinct from the trial’s own design justification and is not observed power. Together, these points show why transparent reporting of estimands, analysis methods, missing-data handling, and estimates with uncertainty is essential for evaluating a clinical trial statistically.

14. Limitations

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

The principal limitation for interpreting efficacy is that the registry record does not report a single numerical primary comparison. It gives the primary outcome definition and scale, but not the group means, contrast estimates, confidence intervals, or p-values. The size, direction, and precision of the primary outcome findings therefore cannot be assessed.

The primary endpoint combines repeated ratings across many assessment points and refers to two chemotherapy cycles. The record does not specify the statistical model used, how the cycles were represented in the analysis, or how incomplete ratings were handled. It also does not report the analysis population or outcome-specific group counts. These details are needed to understand the analysis and assess potential effects of missing data.

Although the record identifies a randomized, double-masked, parallel-group phase III design, it does not describe the randomization procedure, allocation concealment, or who was masked. Detailed eligibility criteria are not reported, so the patient population cannot be characterized beyond the stated breast cancer setting and chemotherapy context. The registry does not report the trial’s own sample-size justification, multiplicity approach, or a complete statistical analysis plan.

The registry lists secondary outcomes and 7 analyses, but does not provide enough information in this record to map all analyses to prespecified questions or evaluate their methods. Safety denominators are substantially more limited than total enrollment, and the record does not explain the safety population in the summary. These limitations concern what can be evaluated from the registry record; they do not establish that unreported procedures or results were absent from the trial’s other documentation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Treatment of Refractory Nausea and Vomiting in Patients With Breast Cancer — NCT03367572.
• Registry record last updated 2025-09-25; status last verified 2025-09.
• Results first posted 2025-09-25.
• 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

NCT03367572 is a completed randomized, double-masked, parallel-group phase III trial sponsored by the University of Rochester NCORP Research Base. It enrolled 1363 participants and studied breast cancer patients receiving chemotherapy. The treatment groups received netupitant/palonosetron hydrochloride and dexamethasone with placebo, prochlorperazine, or olanzapine.

The primary outcome is average nausea on a 7-point scale across repeated assessment points at Cycle 1 and Cycle 2; higher ratings indicate worse nausea. The registry also lists secondary nausea and vomiting outcomes. It reports selected adverse-event counts and no deaths in the listed groups. A single primary outcome comparison and its statistical uncertainty are not reported in the registry record, so efficacy direction, magnitude, and precision cannot be summarized.