A Study of the Safety of Subcutaneously Administered Trastuzumab (Herceptin) in Participants With Early and Locally Advanced Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Safety of Subcutaneously Administered Trastuzumab (Herceptin) in Participants With Early and Locally Advanced Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (NCT01940497), a non-randomized phase 3 study. The primary outcome is Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a phase 3, prospective, multicenter, open-label, non-randomized study with two sequential cohorts. The registry records enrollment as 240 and status as completed. The first 120 participants received subcutaneous trastuzumab from a vial, and the subsequent 120 received it using a single-use injection device. The record does not describe random allocation, masking, or a concurrent control group. Because the cohorts entered in sequence, the study is not a randomized comparison of delivery methods.

Each group received trastuzumab at 600 mg every 3 weeks. The registry describes four cycles alongside adjuvant or neoadjuvant chemotherapy, followed by 14 cycles of trastuzumab alone. The chemotherapy regimens could include doxorubicin followed by paclitaxel or docetaxel. The registry describes treatment as lasting 1 year. It does not report enough detail in this record to reconstruct individual treatment changes, adherence, or reasons for stopping treatment.

The primary outcome is the percentage of participants with TEAEs, reported within adjuvant and neoadjuvant groups for each arm. Secondary outcomes include actual trastuzumab dose, treatment duration, concomitant medications, pathological complete response in neoadjuvant groups, recurrence-related outcomes, disease-free survival, deaths and overall survival. The registry describes follow-up for 24 months after the last participant received the last study-treatment dose, with earlier end of follow-up in case of withdrawal, loss to follow-up or death. This follow-up description should not be confused with the primary endpoint window, which ends 28 days after the participant’s last trastuzumab dose.

The registry record does not report a randomized treatment contrast or a protocol-based sample-size justification. Consequently, the design is principally descriptive for the posted safety information. Results across the vial and SID groups require caution: the treatment delivery method differs, but so does the cohort sequence, and the study does not provide randomization to separate those influences.

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: Out of 263 screened participants, 240 participants were enrolled in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population

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.

Population: Intent-to-treat (ITT) population included all enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), measured over Day 1 up to 28 days after last dose of trastuzumab (up to approximately 1 year).

The primary endpoint is the percentage of participants with treatment-emergent adverse events. The registry defines an adverse event as an untoward medical occurrence in a participant who received study drug, regardless of whether a causal relationship was considered possible. A TEAE is an event starting on the day of, or after, the first trastuzumab administration and occurring within 28 days after the last trastuzumab dose. The registry gives the timeframe as Day 1 up to 28 days after last dose of trastuzumab, up to approximately 1 year.

This endpoint is useful for describing the occurrence of adverse events during treatment and the specified post-treatment window. Reporting the percentage of participants with an event expresses frequency relative to the group being described; the accompanying counts help show how many participants were affected. However, an event classified as treatment-emergent is not automatically caused by treatment. The endpoint definition is based on timing, not proof of attribution.

The registry says the outcome was analyzed and reported separately for adjuvant and neoadjuvant chemotherapy groups within each arm. This stratification matters because treatment context may differ across those groups. The information summarized in the registry record does not include an overall endpoint estimate, confidence interval, or inferential test. It also does not specify how repeated events in the same participant contributed to the participant-level percentage. The posted safety counts should therefore be read as descriptive records, not as a complete inferential analysis of the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: whether a participant experienced at least one qualifying treatment-emergent adverse event during the defined period. In general, a percentage for a binary outcome is intended to summarize the proportion of participants with the event in a specified group. Counts and denominators are essential to interpreting that proportion, because the same event count can convey different levels of precision in groups of different sizes. The registry information gives group counts for serious and other adverse events, but it does not give a confidence interval for the primary outcome.

What does a confidence interval add?

As a general statistical explanation, a confidence interval describes uncertainty around an estimated quantity under a specified method. It helps readers distinguish a relatively precise estimate from one compatible with a wider range of values. A confidence interval is not a guarantee that the true value lies within its bounds, and it does not resolve design limitations such as non-random allocation. The registry record does not report confidence intervals for the primary endpoint, so its precision cannot be assessed from an interval estimate.

Why does the study design limit comparison?

Random allocation is a general design method for balancing, on average, both known and unknown participant characteristics between treatment groups. This study is explicitly non-randomized. The vial cohort preceded the SID cohort, so device and cohort order coincide. A difference in observed safety counts could reflect the device, but it could also reflect differences in participants, clinical practice, follow-up, or other factors that vary over time. The registry record does not report an adjusted comparison that would address such factors. Therefore, the observed group data do not isolate a device effect.

Open-label treatment means masking was absent, according to the registry. In general, awareness of treatment can affect reporting, assessment, or management of events, although the information does not show whether or how that occurred in this study. The adverse-event definition includes events without regard to a possible causal relationship, which is useful for broad safety surveillance but means event counts should not be read as counts of confirmed drug reactions.

What do the serious-event counts represent?

The registry reports serious adverse-event counts separately from counts for other adverse events, within adjuvant and neoadjuvant groups. Those are descriptive counts of participants affected, paired with the group’s listed count at risk. They are not rates adjusted for follow-up time, and the record does not provide event-level timing or recurrent-event details in the information. The listed serious-event terms and percentages add descriptive context, but the registry information does not specify their denominators or provide comparative uncertainty measures.

For a binary outcome, a participant is generally classified according to whether the event occurred at least once; multiple events in one participant may not translate into multiple affected participants. This is a general distinction between participant-level proportions and event counts. The record does not explain in detail how recurrent events were handled for each reported measure, so those approaches should not be assumed. The primary endpoint is described as a percentage of participants, while the safety details include affected-participant counts.

How should sample-size calculations be interpreted?

The registry record says that any sample-size illustrations are planning illustrations computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between arms and a normal approximation. The stated effect to detect is a fraction of the observed effect. These illustrations are not the trial’s own design justification and are not observed power. Planning illustrations describe hypothetical future study requirements under chosen assumptions; they do not establish the probability that this completed study detected an effect. The record does not report the trial’s sample-size justification.

The registry also indicates that time-to-event illustrations use a total number of events, while other illustrations use participants per arm. That distinction is general: time-to-event calculations are often driven by event information, whereas binary-outcome planning commonly concerns the number of participants in each group. No calculated illustration values are included in the information, so no specific planning requirement can be interpreted.

No inferential analysis records are listed in the registry information. The record does not report p-values, model specifications, covariate adjustments, confidence intervals, or a statistical analysis plan. It is therefore not possible to describe which statistical test or model generated an inferential result for the primary endpoint. A descriptive account of posted counts is appropriate; a claim of statistical significance or equivalence is not supported by the information recorded.

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("Trastuzumab (Vial): Adjuvant", "Trastuzumab (Vial): Neoadjuvant", "Trastuzumab (SID): Adjuvant", "Trastuzumab (SID): Neoadjuvant")
n      <- c(95, 20, 92, 21)
events <- c(94, 20, 82, 20)
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  Trastuzumab (Vial): Adjuvant  95  94  98.9  94.3  100.0  94.3  99.8  94.3  99.7
ARM  Trastuzumab (Vial): Neoadjuvant  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9
ARM  Trastuzumab (SID): Adjuvant  92  82  89.1  80.9  94.7  81.1  94.0  81.1  93.9
ARM  Trastuzumab (SID): Neoadjuvant  21  20  95.2  76.2  99.9  77.3  99.2  77.2  98.9

11. Multiplicity, Missing Data and Analysis Populations

The study lists multiple outcomes, including treatment-emergent adverse events, dose administered, treatment duration, concomitant medications, pathological complete response in neoadjuvant groups, recurrence-related outcomes, disease-free survival, deaths and overall survival. Considering many outcomes can raise a general statistical issue called multiplicity: the more hypotheses tested, the greater the chance that some results appear unusual by chance. The registry information does not report a multiplicity adjustment, a hierarchy of confirmatory outcomes, or a statistical analysis plan. It is not possible to determine whether any adjustment was planned or applied.

The record lists no analysis records for these outcomes in the information. It does not report inferential comparisons, confidence intervals, or tests for the primary endpoint. The absence of reported analysis details means the posted counts should not be presented as statistically significant findings. It also means the interpretation cannot rely on an unreported model or adjustment.

Missing data handling is not reported in the registry record. The registry describes follow-up ending earlier in case of withdrawal, loss to follow-up or death, but it does not state how missing endpoint status, incomplete follow-up, or participants without evaluable data were handled in each analysis. The record does not describe imputation, censoring rules for the primary endpoint, or sensitivity analyses. No assumptions about these procedures should be made.

The primary outcome specifies the safety population, but further analysis-population definitions are not reported in the registry record. The available information does not establish whether every enrolled participant contributed to each endpoint, or how deviations from treatment or incomplete observation were handled. Those details are important for assessing the denominator and potential bias, particularly in a non-randomized study.

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: atrial fibrillation (5.0%), pleuropericarditis (5.0%), gastroenteritis (5.0%), intervertebral disc protrusion (5.0%), vomiting (4.8%).

The serious adverse-event entries are reported separately for the four device-by-chemotherapy groups. The vial adjuvant group lists 5 affected among 95 at risk, and the vial neoadjuvant group lists 3 among 20. The SID adjuvant group lists 7 among 92, while the SID neoadjuvant group lists 2 among 21. These are group-specific counts, not evidence of a causal relationship or a randomized comparison. The registry separately lists counts for other adverse events: 92 among 95, 20 among 20, 79 among 92 and 18 among 21, respectively.

The serious-event terms include atrial fibrillation, pleuropericarditis, gastroenteritis and intervertebral disc protrusion, each reported at 5.0%, as well as vomiting and neutropenia, each at 4.8%. The registry information does not state the denominators for these term percentages or show their distribution across the four groups. They cannot be used to rank device safety.

The adverse-event definition does not require a suspected causal link. The counts describe events recorded during the study, not confirmed treatment reactions. Deaths are listed separately as 5, 1, 0 and 1 across the groups; the record does not establish their relation to treatment or provide survival estimates in the information.

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

The registry record describes a study of subcutaneous trastuzumab delivered through a vial in the first cohort and through a single-use injection device in the subsequent cohort. It records adverse-event counts within adjuvant and neoadjuvant groups and defines a treatment-emergent event by its timing relative to trastuzumab administration. These details help characterize what safety observations were collected and during what period.

The results do not show that a device caused or prevented an adverse event. The event definition includes occurrences regardless of whether a causal relationship was considered possible. The counts also do not establish that the two delivery methods have equal or different safety profiles. The non-randomized, sequential design cannot separate a device difference from cohort order or other group differences, and the registry record does not provide adjusted estimates or uncertainty intervals for a comparative effect.

The figures also do not describe every aspect of clinical outcome. The registry lists secondary outcomes concerning pathological response, recurrence, disease-free survival and overall survival, but the information does not provide their results or analyses. The primary endpoint is an adverse-event measure; it is not an efficacy endpoint. No conclusion about efficacy follows from these safety counts.

For readers, the most defensible interpretation is that the record offers descriptive safety observations in the specified groups and time window. The available information does not establish causation, comparative effectiveness, statistical significance, or equivalence. Missing-data procedures, analysis populations beyond the stated safety population, and formal inferential methods are not reported in the registry record. Those omissions limit how precisely the observations can be compared or generalized.

14. Why This Trial Matters Statistically

This study is statistically notable because it places a delivery-device question in a non-randomized, sequential design. The vial and SID groups were enrolled in order rather than assigned concurrently at random. That choice matters for interpretation: device type and cohort timing are intertwined, so a difference in observed adverse events would not isolate the effect of the device. This is a central design limitation, not a technical detail that can be resolved by comparing raw counts.

The study also reports safety information by adjuvant and neoadjuvant context. That makes the clinical grouping visible, but it leaves relatively small groups alongside larger ones, and the registry does not provide uncertainty intervals for these counts. As a general statistical principle, estimates from smaller groups can be less precise, so apparent variation between subgroups may be unstable. Without formal uncertainty estimates, readers should avoid treating modest count differences as evidence of a real underlying difference.

The primary outcome uses a broad timing-based definition of treatment-emergent events. This is useful for describing what occurred during exposure and shortly afterward, while also underscoring that timing alone does not demonstrate causality. The record’s separate listing of serious and other events gives a more detailed safety picture, but it does not replace a prespecified analysis plan or a randomized comparison.

Finally, the registry identifies multiple clinical outcomes but does not report analysis details or results for them in the information. This highlights a general distinction between registering outcomes and reporting inferential evidence. For statistical interpretation, knowing the endpoint definition, analysis population, missing-data approach and uncertainty around estimates is as important as knowing the observed counts.

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.

The most important trial-specific limitation is the non-randomized, sequential allocation. The first 120 participants received the vial presentation and the subsequent 120 received the SID presentation. The study therefore does not provide a randomized, concurrent comparison, and possible differences between groups cannot be attributed to the device alone. The registry itself cautions that the arms are not a like-for-like control comparison.

The primary outcome is analyzed within adjuvant and neoadjuvant groups, but the registry information does not provide confidence intervals, hypothesis tests, or adjusted estimates. It is not possible to determine the precision of comparisons or whether participant or care differences were taken into account. The record does not report the statistical analysis plan, sample-size justification, multiplicity approach or interim analyses.

Missing-data and analysis-population procedures are not reported in the registry record. Although the safety population is named, further details about evaluability and endpoint denominators are absent. The record also does not explain how recurrent events were treated in participant-level percentages. These omissions limit assessment of potential bias and the exact meaning of each estimate.

The serious adverse-event term percentages are reported without denominators or group-specific breakdowns in the information. Death counts are listed, but their relationship to treatment and their time-to-event analysis are not described. Secondary outcomes are named, but their results are not included in the information. Follow-up is described for 24 months after the last participant’s last dose, but that does not supply outcome-specific follow-up completeness or missingness details.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Safety of Subcutaneously Administered Trastuzumab (Herceptin) in Participants With Early and Locally Advanced Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer — NCT01940497.
• Registry record last updated 2020-11-03; status last verified 2020-10.
• Results first posted 2017-07-02.
• 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

The registry describes NCT01940497, a completed phase 3, multicenter, open-label, non-randomized study sponsored by Hoffmann-La Roche. It records enrollment of 240 participants with early and locally advanced HER2-positive breast cancer. The first 120 participants received subcutaneous trastuzumab by vial, and the subsequent 120 received it using a single-use injection device.

The primary outcome was the percentage of participants with treatment-emergent adverse events, assessed from the first trastuzumab administration through 28 days after the last dose. The registry reports safety counts within adjuvant and neoadjuvant groups. It also lists secondary outcomes concerning treatment exposure, pathological response, recurrence, disease-free survival, deaths and overall survival.

The design does not support a randomized, like-for-like comparison between delivery methods. The registry record does not report inferential analyses, confidence intervals, missing-data methods, or a sample-size justification. The posted safety information is therefore descriptive and should be interpreted within those limits.