Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib (NCT04327700), a na phase 2 study. The primary outcome is Progression-Free Survival.

2. Clinical Question

This was a Phase II study in advanced hepatocellular carcinoma after first-line systemic therapy. The registry's summary frames the efficacy question as whether progression-free survival with electromagnetic fields plus regorafenib could be assessed in relation to historical results for regorafenib alone. That framing is not the same as a randomized comparison: the study record identifies a single treatment group and lists allocation as not applicable.

The population description allows a range of prior first-line systemic treatments, including sorafenib, lenvatinib, or an experimental therapy. The record also states that people who had received either regorafenib or electromagnetic fields would be excluded. Other eligibility details, including disease characteristics beyond advanced hepatocellular carcinoma and the operational definition of prior treatment, are not reported in the registry record.

The primary question concerns PFS at 12 weeks. Secondary outcomes listed in the record include overall survival, disease control, adverse events, a historical adverse-event comparison, and change in alpha-fetoprotein levels. The registry record does not report results for these outcomes. Enrollment was 2 and the study status is terminated, so the available record is a description of a very small study rather than a comparative estimate that can establish how outcomes differ between treatment strategies.

3. Trial Design

The registry identifies this as a Phase II study with a single group: participants received regorafenib and TheraBionic. Allocation is listed as not applicable, and masking is listed as none. The record therefore does not describe random assignment or blinded treatment assessment. It planned to examine efficacy in relation to historical data for regorafenib alone, rather than enrolling a contemporaneous control group within the study.

The device is described as a battery-driven radiofrequency electromagnetic field generator. Its metal mouth spoon antenna is placed on the anterior part of the tongue during treatment. Regorafenib is described as a 40 mg tablet administered orally. Treatment frequency, treatment duration, dose-modification rules, adherence procedures, and details about how the two treatments were coordinated are not reported in the registry record.

The study started on 2021-01-26, had a primary completion date of 2024-05-31, and is listed as terminated. Enrollment was 2. The reason for termination and whether the planned enrollment was reached are not reported in the registry record. The record does not give a planned enrollment target or a timeline for recruitment and follow-up beyond those dates.

A historical comparator can give context, but it does not create the balance that randomization seeks in a concurrent comparison. Differences in eligibility, patient characteristics, outcome assessment, follow-up, and care over time can influence comparisons between a new study group and historical data. The registry summary does not report the source details or methods for selecting and aligning historical data. Consequently, it is not possible to assess from the record whether the historical comparison would have been sufficiently comparable.

The record lists one analysis and several secondary outcomes, but does not describe the statistical analysis plan, analysis populations, or handling of incomplete follow-up. Those details, as well as any protocol deviations, are not reported in the registry record. The listed design and enrollment are enough to distinguish the study from a randomized trial, but not enough to reconstruct the intended analysis or judge whether the analysis followed a prespecified plan.

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 Progression-Free Survival, measured over 12 weeks.

The primary endpoint is progression-free survival at 12 weeks after study enrollment. PFS is a time-to-event concept: it describes the time until disease progression or death, with follow-up and censoring rules determining how each participant contributes to the analysis. The registry describes assessment in days and defines progression using change in the sum of the longest diameters of target lesions relative to the smallest recorded sum, together with an absolute increase requirement.

The record specifies that a participant who begins post-study anti-tumor therapy before radiologic progression is censored at that date. Censoring means that follow-up for the endpoint stops at a specified time without treating that point as a progression event. It is important because the timing and reason for censoring can affect interpretation of a time-to-event estimate. The full operational rules for assessment schedules, missing scans, and other censoring situations are not reported in the registry record.

PFS is used in oncology studies because it focuses on whether disease progression or death has occurred over a defined follow-up period. It is distinct from overall survival, which concerns death from any cause, and from disease control, which is listed separately as a secondary outcome. A PFS assessment at a fixed time point can be presented as a count or proportion, while analyses of time until an event can use methods that account for different follow-up times. The registry record does not report which inferential method was used for the primary endpoint.

The outcome description contains a progression definition and follow-up rules, but the registry record does not report the observed PFS result, an uncertainty interval, or a comparison estimate. Thus, the endpoint can be described, but its result cannot be interpreted quantitatively from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design estimate?

A single-group study observes outcomes among participants who receive the study treatment. It can describe what was recorded in that group, but it does not directly estimate a randomized difference between treatment strategies. The registry describes a historical comparison as the study's efficacy context, but does not report details of that comparison. In general, a historical reference may differ from a current study group in eligibility, measurement, follow-up, or care. Those differences can make it difficult to attribute an observed contrast to treatment alone.

Random allocation is one way to reduce systematic differences between groups at baseline. This record lists allocation as not applicable and describes one group. Masking is listed as none. These design features do not mean that the outcomes are invalid; they do mean that the kind of inference available is limited compared with a randomized, masked comparison. The registry record does not report any other measures intended to reduce bias in assessment or comparison.

How should PFS be understood?

Progression-free survival is a time-to-event outcome. In general, the analysis follows participants from a defined starting point until a specified event or censoring. For this study, the stated starting point is enrollment, and the endpoint is assessed at 12 weeks. The registry defines progression using tumor-measurement criteria and includes death in the endpoint description. It also specifies censoring when post-study anti-tumor therapy begins before radiologic progression.

Time-to-event methods are useful when participants have different lengths of follow-up or when some participants have not had the event by the time observation ends. Censoring allows available follow-up to contribute without claiming that an unobserved event did or did not occur after follow-up stopped. A key general assumption is that the censoring process does not systematically conceal a different event risk in a way that distorts the estimate. Whether that assumption is plausible depends on why follow-up ends and on the analysis approach. The registry record does not report censoring counts, reasons, or the method used to estimate PFS.

The primary outcome is described as a participant count at a time point, while its definition also describes a period from enrollment to progression, last follow-up, or death. The registry record does not report the numerical result or explain the exact calculation used to convert follow-up information into a reported 12-week result. A reader should distinguish the endpoint definition from an observed estimate: a definition identifies what the study intended to measure, but is not itself an outcome result.

What does an uncertainty interval add?

In general, a confidence interval gives a range of values compatible with the data under a specified statistical procedure. It communicates precision as well as the point estimate. A narrow interval indicates more precision than a wide interval, while both the estimate and its interval require careful interpretation in light of study design and assumptions. The registry record does not report a PFS estimate or confidence interval, so the precision of the primary outcome cannot be assessed from the posted information.

A p-value, in general, measures how unusual the observed data would be under a specified null model and its assumptions. It is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. No primary endpoint p-value is reported in the registry record. With a single group and a historical reference, a p-value would also depend on how the reference data and comparison were defined; those details are not reported.

Why does over-dispersion matter for counts?

For a binary outcome, each participant can be classified according to whether an event occurred, and the observed count can be modeled using a binomial framework under suitable assumptions. Generalized models may use a binomial mean structure when the variability follows the assumptions of that framework. Over-dispersion means the observed variation exceeds what the model expects. If it is ignored, standard errors can be too small and intervals or tests can appear more decisive than warranted. Alternative variance models or robust methods can address some forms of over-dispersion, but the appropriate choice depends on the data and design.

The registry labels the primary measure as a participant count and supplies no dispersion value. It does not report a model, standard error, confidence interval, or adjustment for over-dispersion. The general concepts therefore explain possible methods, not methods confirmed as used in this study.

How should planning illustrations be read?

Sample-size planning uses assumptions about the target effect, variability, significance level, power, allocation, and analysis method. A planning calculation answers a prospective question: what enrollment might be needed under those assumptions? It does not measure the probability that a completed study has found a true effect, and it is not observed power. The record's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as stated fractions of the observed effect. For time-to-event outcomes, the stated planning convention concerns the total number of events; for other outcomes, it concerns participants per arm.

Those assumptions are not a description of this trial's actual design, which is single-group, and the record does not provide the numerical planning outputs or an observed effect estimate. These planning conventions cannot be used to infer that the study enrolled enough participants or that it had a particular achieved power. The record does not report its own sample-size justification or a prospective design calculation. Planning illustrations should be treated as hypothetical, assumption-dependent exercises rather than evidence about the completed study.

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("Regorafenib and TheraBionic")
n      <- c(2)
events <- c(2)
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  Regorafenib and TheraBionic  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists secondary outcomes in addition to the primary PFS outcome. They include overall survival, percentage of participants with disease control, adverse events by body system, a Grade 3+ adverse-event comparison with a historical trial, and change in alpha-fetoprotein levels. Considering multiple outcomes raises a general multiplicity issue: the more statistical questions examined, the greater the chance of finding an apparently notable result by chance if each is tested separately. Methods such as prespecifying a primary outcome, controlling a family-wise error rate, or using a hierarchical testing strategy can address different multiplicity goals. The registry record does not report whether any such approach was planned or used.

Missing outcome information also matters. The registry record does not report how many participants had endpoint assessments, how much follow-up was available, whether any assessments were missing, or how missing measurements were handled. For PFS, censoring rules are described for starting post-study anti-tumor therapy before radiologic progression, but censoring counts and additional operational rules are not reported. In general, a missing assessment is not automatically equivalent to no event; its treatment in an analysis depends on the estimand and analysis plan.

The record does not define analysis populations, such as whether all enrolled participants would be included regardless of treatment exposure, or how deviations from treatment would be handled. It also does not report an intention-to-treat approach, a per-protocol approach, or sensitivity analyses. With enrollment of 2, transparency about each participant's follow-up and endpoint status would be important for understanding a reported result, but those details are not reported in the registry record.

No multiplicity adjustment, missing-data strategy, or analysis-population definition should be assumed. These omissions limit the ability to assess how robust any result might be to alternative outcome definitions or analytic choices.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists 0 serious adverse events among 2 participants at risk in the Regorafenib and TheraBionic group. It also lists 2 other adverse events among 2 at risk and 1 death. These are recorded counts, not estimates of comparative risk. The record does not give serious adverse-event terms, and no top serious-event terms are listed.

Serious events and other adverse events are separate categories in the record. The count of other adverse events should not be interpreted as a count of people with a particular type or severity of event, because the record does not provide event-level descriptions or clarify whether a participant could contribute more than one event. The record also does not provide a time window for these safety counts or explain the criteria used to classify events.

A death recorded in a study does not, by itself, establish that treatment caused the death. The registry record does not state the cause of death or its relationship to study treatment. Likewise, a recorded count of 0 serious events in this group does not demonstrate that serious risks are absent; the enrollment was 2 and the record does not provide detailed follow-up or event ascertainment information. The safety figures should be read as limited descriptive counts, not as a complete estimate of treatment safety or a comparison with regorafenib alone.

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

The registry record establishes that a Phase II study of regorafenib with TheraBionic was conducted as a single-group study and is listed as terminated. It reports enrollment of 2 and provides limited adverse-event counts. It also identifies PFS at 12 weeks as the primary outcome and describes how progression and some censoring were defined. These registry entries describe the study's intent and the information recorded about its conduct.

The record does not report the primary PFS result, an overall survival result, a disease-control result, or results for the other listed secondary outcomes. It does not report a treatment-effect estimate, an uncertainty interval, or an inferential test. The treatment's comparative effect therefore cannot be quantified from the registry record. The stated historical comparison does not convert this single-group study into a randomized comparison, and the record does not describe how historical data were selected or analyzed.

The record also does not explain why the study was terminated. It cannot establish whether termination was due to recruitment, safety, efficacy, operational constraints, or another reason. No such explanation should be inferred from the status alone.

In general, a study result is interpreted through both its estimate and its uncertainty, alongside the design and quality of outcome ascertainment. A small enrollment and missing outcome reporting leave substantial uncertainty about the PFS question. The safety counts provide only a limited description and cannot determine causation or compare safety with another treatment strategy.

Accordingly, the posted information supports a cautious account of design, eligibility context, endpoint definition, enrollment, status, and recorded safety counts. It does not support a claim that the combination improves or worsens PFS, a claim of equivalence to regorafenib alone, or a conclusion that treatment-related risks are absent.

14. Why This Trial Matters Statistically

This study is statistically notable because its stated efficacy question involves a historical comparison, while its registered design is single-group. That distinction is important when interpreting evidence. A randomized concurrent control can help make groups comparable at baseline through assignment; historical comparisons depend on the comparability of data collected in different settings or periods. Understanding that difference prevents a descriptive study result from being mistaken for a randomized treatment effect.

The endpoint also illustrates why definitions and results must be kept separate. The registry provides a PFS definition, including tumor-measurement criteria and a censoring rule for post-study anti-tumor therapy. Those details help identify what was intended to count as progression and how follow-up could end. But the definition alone does not reveal how many participants were progression-free, how long follow-up lasted, or how precisely the outcome was estimated. The result itself is not reported in the registry record.

Enrollment of 2 further emphasizes the difference between describing observed cases and estimating a treatment effect with useful precision. A count in a small single group can be informative as a record of what was observed, but without a reported outcome estimate and uncertainty interval it cannot answer a comparative efficacy question. Safety counts require the same restraint: they can document recorded events without establishing causality or ruling out risks.

Finally, the listed secondary outcomes create questions about analysis planning, multiplicity, missing data, and outcome reporting. The registry record does not provide enough information to assess these methods. The statistical significance of the record is therefore methodological rather than a quantitative conclusion about efficacy: it shows why design, endpoint definitions, complete results, and uncertainty measures are all needed before interpreting clinical comparisons.

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.

Several limitations specific to this study restrict interpretation. It is registered as a single-group study with allocation not applicable and no masking. The efficacy context is historical regorafenib-alone data, but the registry record does not identify the historical dataset, its eligibility criteria, or how the comparison would account for differences in patient mix, outcome measurement, follow-up, or care over time. A like-for-like control comparison is not described.

Enrollment was 2, and the study status is terminated. The reason for termination, planned enrollment target, recruitment details, and whether follow-up was complete are not reported in the registry record. The record does not report the primary PFS outcome or any numerical results for the listed secondary outcomes. It also omits estimates of uncertainty and inferential results, limiting assessment of both the direction and precision of outcomes.

The endpoint description gives progression criteria and a censoring rule, but the registry record does not report assessment schedules, censoring counts, missing scans, or the detailed analysis method. It does not specify analysis populations, handling of protocol deviations, or sensitivity analyses. These omissions prevent a detailed appraisal of how endpoint data were converted into an estimate.

Safety information is also limited. The record gives group-level counts but no event descriptions for the serious-event category, no cause or treatment relationship for the death, and no safety observation window. The reason for termination and the completeness of adverse-event follow-up are not reported. The record therefore supports only a narrow descriptive account of study conduct and recorded safety counts, not a complete evaluation of efficacy or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib — NCT04327700.
• Registry record last updated 2026-03-05; status last verified 2026-03.
• Results first posted 2026-03-05.
• 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

This is a Phase II, single-group study of TheraBionic and regorafenib for patients with advanced hepatocellular carcinoma after first-line systemic therapy. The device is described as a battery-driven radiofrequency electromagnetic field generator with a tongue-placed antenna; regorafenib is described as a 40 mg oral tablet. The primary outcome is PFS at 12 weeks after enrollment, with progression and censoring criteria described in the registry record.

The study started on 2021-01-26, had a primary completion date of 2024-05-31, enrolled 2, and is listed as terminated. The registry reports 0 serious adverse events among 2 at risk, 2 other adverse events among 2 at risk, and 1 death. It does not report the primary PFS result, results for the listed secondary outcomes, the reason for termination, or a detailed statistical analysis plan. Its historical comparison aim should not be interpreted as a randomized comparison.