Recombinant Human Hyaluronidase in Treating Lymphedema in Patients With Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Recombinant Human Hyaluronidase in Treating Lymphedema in Patients With Cancer (NCT01928030), a na phase 1, phase 2 study. The primary outcome is Treatment-related Adverse Events.

2. Clinical Question

3. Trial Design

This is a phase 1-2 investigational study of recombinant human hyaluronidase for secondary lymphedema following local management of malignancy. Stanford University is listed as the sponsor. The study began in 2013-12, had a primary completion date of 2015-11, and is now listed as terminated. The registry record reports enrollment of 3 participants.

The design is single-group, allocation is listed as not applicable, and masking is none. There is no separate control arm described, so the study does not provide a randomized comparison of treatment with another intervention or with no treatment. The regimen descriptions distinguish phase 1 from phase 2: 450 units administered subcutaneously on days 1, 3, 5, and 7 in phase 1, and 900 units administered subcutaneously on days 1 to 21 in phase 2. The registry record does not explain how participants were assigned to these phase-specific schedules or whether any participant received both.

The study summary identifies side effects and dose as topics of interest, and says the study was intended to assess how well the treatment works. Reduction in forearm volume is listed as a secondary outcome. The reason the study was terminated, the planned sample-size justification, and any interim analysis procedures are not reported in the registry record. The small enrollment and absence of a control group are important when interpreting what the posted results can establish.

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 Treatment-related Adverse Events, measured over Up to 1 year.

The primary endpoint counts participants with treatment-related adverse events during follow-up up to 1 year. The registry definition includes any untoward medical occurrence or worsening of a pre-existing medical condition in a participant who received recombinant human hyaluronidase, when the event was judged possibly, probably, or definitely related to treatment. The endpoint is therefore based on participants with an event, rather than on the total number of event episodes.

Safety endpoints are used to describe harms observed during a study and to identify events considered related to the intervention. The relationship judgment is part of the endpoint definition; it is not the same as proving that treatment caused an event. In a single-group study, event counts describe what occurred among treated participants, but they cannot by themselves distinguish treatment-related risk from events that might also occur without treatment.

The registry record lists reduction in forearm volume as a secondary outcome, but does not report its result or an analysis. It also does not report a definition, measurement method, or analysis time for that secondary outcome. Thus the available primary endpoint information is limited to adverse-event counts, rather than evidence about change in lymphedema volume.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is expressed as a count of participants who had a qualifying treatment-related adverse event. This differs from counting event episodes: a participant with more than one event would still contribute as a participant with an event for a participant-level count. The posted safety information gives the number at risk and the number affected for serious and other adverse events. These counts are direct descriptive summaries, not model-based estimates.

For a binary outcome, each participant is classified according to whether the specified event occurred. A proportion can often be used to describe the fraction affected, but with a very small group it is important not to treat that observed fraction as a precise estimate of the rate in a larger population. The registry record reports counts, and no uncertainty interval or inferential analysis is reported.

Why does the absence of a control group matter?

A single-group study can describe events observed after treatment, but it does not provide a concurrent group for comparison. Without such a group, the observed count cannot separate events attributable to treatment from background events or other influences. A comparison across the phase-specific regimens also cannot be assumed: the record does not describe random assignment, and it does not explain the participant-level sequence or allocation to the phase 1 and phase 2 schedules.

Randomization, when used, helps make groups comparable on average by assigning treatment independently of participant characteristics. Masking can reduce some forms of bias in assessment or reporting. This record lists allocation as not applicable and masking as none. These design features mean that a comparative interpretation is not supported by the posted study design.

What can confidence intervals and tests add?

In general, a confidence interval expresses the range of values reasonably compatible with observed data under a statistical model and its assumptions. It communicates precision as well as the estimate itself. A significance test evaluates how compatible the data are with a specified null hypothesis under a model. Neither can make an uncontrolled study into a randomized comparison, and neither would resolve uncertainty arising from sparse data or incomplete outcome reporting. No confidence interval, test result, or outcome analysis is reported in the registry record.

For binary outcomes, statistical methods may use approximations that work better when there is enough information in the data. With very few participants or very rare events, approximations can be unreliable, and exact methods or careful descriptive reporting may be considered in general. Here, the registry record supplies the event counts but does not report a statistical method, uncertainty interval, or analysis plan. No inferential result should be inferred from the counts alone.

How should planning illustrations be read?

Sample-size planning asks how many participants might be needed to detect a specified effect under stated assumptions. The planning illustration associated with this record is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the detectable effect expressed as a fraction of the observed effect. It is explicitly a planning illustration, not the trial's own design or observed power.

Those assumptions do not match the registered single-group design: equal allocation between two arms is not the design described for this study. The illustration should therefore not be read as a recruitment target used by the sponsor, evidence that the study had adequate power, or a basis for interpreting efficacy. The trial's sample-size justification is not reported in the registry record. No planning estimate can replace a reported analysis of the outcomes.

Why can over-dispersion matter in other analyses?

In general, over-dispersion occurs when observed variability is greater than a statistical model expects. It can make standard errors too small if the model does not account for that extra variation, resulting in overly narrow intervals or misleading tests. This concept is relevant to some count-data models, but the posted primary result is a participant count for a binary event, and no count-model analysis is reported. There is no basis in the registry record to claim that over-dispersion was assessed or to describe it as a feature of this study's results.

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("450 Units Recombinant Human Hyaluronidase (rHuPH20")
n      <- c(3)
events <- c(1)
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  450 Units Recombinant Human Hyaluronidase (rHuPH20  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome of treatment-related adverse events and a secondary outcome of reduction in forearm volume. It does not report an analysis of either outcome. The number of outcomes listed does not reveal whether formal hypothesis tests were planned, whether any adjustment for multiple testing was intended, or how a primary analysis would have been prioritized. Multiplicity procedures and interim analyses are not reported in the registry record.

When multiple outcomes or repeated statistical tests are examined, the chance of at least one apparently notable result can increase. Statistical approaches for multiplicity can control that issue, but the suitable approach depends on the planned questions and analysis. No multiplicity strategy is reported, so no claim can be made about how testing across outcomes would have been handled. In the absence of reported analyses, there are no efficacy p-values or intervals to interpret.

Missing-data methods, participant-level analysis populations, and the completeness of follow-up are not reported in the registry record. The primary outcome timeframe is up to 1 year, but the record does not state how many participants completed that period or how an incomplete observation would be handled. It also does not report whether all enrolled participants were included in each outcome summary. These omissions matter because safety counts and forearm-volume results can be affected by how missing observations and analysis populations are defined.

The reason for termination and any consequences for data collection are not reported. Without these details, the completeness of outcome ascertainment cannot be evaluated. The posted counts should therefore be read as the recorded participant counts, not as evidence that missing data were absent or addressed by a particular method.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event figures report 0 affected participants among 3 at risk in the recombinant human hyaluronidase group. The other adverse-event figures report 1 affected participant among 3 at risk. These are participant-level counts; they do not state how many separate event episodes occurred. No serious adverse-event terms are listed, and the term associated with the other event is not reported in the registry record.

The primary outcome definition covers untoward medical occurrences or worsening of pre-existing conditions judged possibly, probably, or definitely related to treatment, with a timeframe of up to 1 year. The serious and other adverse-event counts are safety summaries, but the record does not provide individual event descriptions or further detail about relatedness for each event. A zero serious-event count in this small group is not proof that the risk is absent. It is a description of the events recorded among the participants in this study.

Because there is no control group, the counts cannot show whether the event burden differs from what would have occurred under another treatment or without treatment. The reason for termination and the completeness of safety follow-up are not reported in the registry record. These limitations constrain the conclusions that can be drawn from the counts.

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

The record documents a phase 1-2 investigation of recombinant human hyaluronidase in secondary lymphedema and reports enrollment of 3 participants. It provides participant counts for serious and other adverse events. Those counts are useful as a description of what was recorded, but the very limited enrollment means they cannot precisely characterize how frequently events would occur in a wider group.

The study is single-group, with no separate comparator and no masking. Consequently, the event counts cannot establish a difference in safety relative to another intervention or no intervention. The treatment-related classification is part of the endpoint definition, but a judgment that an event may be related does not by itself prove causation. Similarly, observing no serious adverse events in the enrolled group does not establish that serious events cannot occur.

The record lists reduction in forearm volume as a secondary outcome and describes an interest in whether treatment works, but no analyses or results for that outcome are reported. The posted safety counts therefore cannot answer whether forearm volume changed or whether treatment affected lymphedema. No estimate of effect, comparison, or uncertainty for that clinical outcome is reported in the registry record.

The study's terminated status is recorded, but its reason is not. The record also does not explain whether termination influenced follow-up or outcome reporting. As a result, the findings are best understood as limited descriptive safety information from a small, uncontrolled study, rather than a conclusive assessment of efficacy or comparative safety.

14. Why This Trial Matters Statistically

This study illustrates why study design and the amount of information available matter as much as the event count itself. The registry record reports 3 participants in a single-group phase 1-2 study. Participant counts can document events observed in a study, but sparse data cannot reliably characterize the range of outcomes in a broader population. A count of zero is particularly easy to overread: it describes the observed group and does not prove that an event is impossible.

The absence of a control group is also consequential. Even a carefully defined treatment-related event endpoint depends on judgments about whether an event may be linked to treatment. Without a comparison group, the study cannot estimate how event occurrence differs from a relevant alternative. The same issue applies to efficacy: a listed clinical outcome is not evidence of a treatment effect when its result and analysis are not reported.

The record also demonstrates the distinction between trial design and sample-size planning. A planning illustration based on a two-arm assumption is not evidence that this single-group study used that design, and it is not observed power. Planning calculations depend on assumptions and are most useful when they correspond to the actual design and prespecified question.

Finally, status and completeness influence interpretation. The study is listed as terminated, but the reason and any effect on follow-up are not reported. The available record therefore supports a narrow, transparent reading: a small study with descriptive adverse-event counts and no reported efficacy analysis. Recognizing these limits prevents descriptive observations from being mistaken for comparative or definitive conclusions.

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 direct limitation is enrollment of 3 participants. Such a small group provides little information about the frequency or range of adverse events, and it limits the precision of any estimate that might be made from the observed counts. The record reports no uncertainty intervals or statistical analyses to quantify that precision.

The study is single-group, with allocation listed as not applicable and masking listed as none. There is no comparator for separating events observed after treatment from events that might occur for other reasons, and no randomized contrast for assessing treatment effects. The phase 1 and phase 2 dose schedules are described, but the participant-level assignment or sequence is not reported; their descriptions should not be treated as a controlled dose comparison.

The registry record lists reduction in forearm volume as a secondary outcome but reports no result or analysis for it. It does not report an efficacy estimate, analysis method, missing-data approach, analysis population, interim analyses, or multiplicity plan. The sample-size justification is also not reported. The planning illustration uses assumptions for two arms, which do not correspond to the registered single-group design and should not be interpreted as the study's own power or design.

The study is listed as terminated, but the reason is not reported in the registry record. The record also does not state whether all participants completed follow-up up to 1 year, how complete the safety data were, or whether termination affected outcome collection. The serious adverse-event terms are not listed, and the other adverse event is not described. These reporting gaps limit interpretation beyond the counts themselves.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Recombinant Human Hyaluronidase in Treating Lymphedema in Patients With Cancer — NCT01928030.
• Registry record last updated 2017-03-21; status last verified 2016-12.
• Results first posted 2017-02-07.
• 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

NCT01928030 is a Stanford University phase 1-2 study of recombinant human hyaluronidase for secondary lymphedema resulting from local management of malignancy. The study is registered as single-group, with no masking, and enrollment of 3 participants. Its status is terminated. The registry record lists a phase 1 schedule of 450 units administered subcutaneously on days 1, 3, 5, and 7, and a phase 2 schedule of 900 units on days 1 to 21.

The primary outcome is treatment-related adverse events through up to 1 year. The posted safety counts are 0 of 3 participants with a serious adverse event and 1 of 3 with an other adverse event. Reduction in forearm volume is listed as a secondary outcome, but no outcome analyses are reported. The reason for termination, the sample-size justification, and details of missing-data handling and analysis populations are not reported in the registry record. The available findings are descriptive and do not provide a controlled estimate of efficacy or comparative safety.