Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X) (NCT04788147), a non-randomized na study. The primary outcome is Cohort I Recommended RefleXion FDG Dose (RRFD) to Enable the Use of BgRT Planning..

2. Clinical Question

3. Trial Design

BIOGUIDE-X was a completed, non-randomized, sequential study of the RefleXion Medical Radiotherapy System. The registry record lists an enrollment of 30 and a device intervention, the RMRS IDE Device. The study began on 2021-03-26, and primary completion was recorded as 2021-12-20. The listed phase is NA. The study had no masking.

The stated purpose was to assess performance and safety of biology-guided radiotherapy using the system. This included optimizing FDG dosing, assessing the PET imaging subsystem for treatment planning and delivery, considering its role as an interlock, and validating dose delivery in the end-to-end workflow.

The design used sequential cohorts, not randomized allocation. Cohort I was intended to identify the Recommended RefleXion FDG Dose (RRFD). Its primary endpoint concerned participants receiving 15 mCi, completing the RMRS image session, and establishing adequate target activity concentration for BgRT planning. The registry record says dose escalation to 20 mCi was not required.

Cohort II was to begin after the RRFD was determined. Its stated objective was to assess whether BgRT dose distributions generated from Limited Time Sample RMRS PET images obtained at treatment delivery were consistent with the approved BgRT plan. The registry record also lists secondary outcomes for both cohorts, covering imaging agreement, plan generation, physical phantom dose delivery, delivery concordance, localization, image concordance, and FDG-related toxicity.

Because enrollment was sequential and cohorts addressed different questions, cohort results do not constitute a randomized comparison. The registry record does not report a prespecified comparator arm or a protocol-based statistical 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The number of patients that received 15 mCi FDG dose and completed the RMRS image session.

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 Cohort I Recommended RefleXion FDG Dose (RRFD) to Enable the Use of BgRT Planning., measured over During the RMRS imaging session.

The primary endpoint was a count of participants who received an FDG dose of 15 mCi, completed the RMRS imaging session, and established an adequate target activity concentration to enable biology-guided radiotherapy planning. The timeframe was during the RMRS imaging session. It therefore addresses whether the selected imaging dose and workflow reached the stated planning-enablement criteria, rather than comparing clinical outcomes between treatment groups.

The endpoint was used in Cohort I to identify the Recommended RefleXion FDG Dose. The registry record describes 15 mCi as the starting dose, based on preliminary physics studies conducted before the study, and states that escalation to 20 mCi was not required. That statement describes the dose-escalation decision; it does not provide the number of participants who met the endpoint or establish how many had adequate imaging activity.

The numerical primary-endpoint result is not reported in the registry record. Without the count meeting the criteria and its analysis population, the posted record does not allow readers to assess the observed success frequency or its precision. The endpoint also does not, by itself, establish performance across all listed secondary outcomes or clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary endpoint, an individual is classified as meeting or not meeting a defined condition. A count reports how many participants fall into the event category. For the primary endpoint, the condition combines receipt of the 15 mCi dose, completion of the RMRS imaging session, and adequate target activity concentration for planning. The registry record describes the endpoint as a count, but does not report its numerical result. Without the count and the number assessed, it is not possible to interpret the observed frequency or its uncertainty.

What does a count tell the reader?

A count is directly interpretable as the number of participants meeting a criterion, provided the analysis population is clear. The denominator matters because it identifies how many participants could have contributed to that count. Enrollment of 30 is the overall study enrollment; it should not be assumed to be the denominator for every cohort or endpoint. The registry record does not report the primary endpoint denominator or the number of participants with missing endpoint information.

When a binary result is presented with a confidence interval, the interval describes the statistical uncertainty around an estimated event frequency under the analysis method used. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from the posted information. A confidence interval would not, by itself, correct for bias from selection, missing data, or study design.

Why does the sequential design matter?

The study was non-randomized and sequential. Cohort I addressed identification of the recommended FDG dose, while Cohort II was intended to assess agreement between dose distributions generated using PET images from treatment delivery and the approved plan. This means that cohort membership was tied to study sequence and objectives rather than random assignment. Comparisons between the cohorts would therefore not have the interpretation of a randomized treatment comparison. Their outcomes answer different questions and may involve different participant sets.

The record lists no masking. In general, masking can reduce the influence of knowledge of group or treatment assignment on assessment or conduct, depending on the study. The registry record does not report additional safeguards or assessment procedures that might have addressed potential influence in this unmasked design. This is relevant to interpreting assessments involving imaging agreement, localization decisions, or plan consistency, but it does not establish that any particular assessment was biased.

How should planning illustrations be understood?

The sample-size illustrations are described as planning calculations based on an observed effect, not as the trial's own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. For time-to-event tables, the stated quantity is the total number of events; for other outcomes, it is participants per arm. The numerical illustration values are not reported in the registry record.

Those assumptions do not match the study's sequential, non-randomized cohort structure as a like-for-like two-arm comparison. Any such figures are planning illustrations, not observed power, and do not establish that the actual study was designed around those assumptions. The registry record does not report the trial's own sample-size justification, target precision, or a formal power calculation. No new sample-size interpretation can be inferred from the total enrollment alone.

What statistical plan is reported?

The registry record lists 12 outcome measures and one analysis, but does not describe the statistical analysis procedures. The specific tests, estimation methods, confidence-interval methods, covariate adjustments, handling of repeated observations, and analysis populations are not reported in the registry record. The primary endpoint is described as a count, but no further model or inferential procedure is stated. It would therefore be inappropriate to assign a particular test or model to the analysis.

General statistical interpretation also depends on the relationship between the question and the method. A method for estimating a single cohort's event frequency differs from a method for comparing groups, and a comparison requires a meaningful comparator. Here, the stated design does not provide a randomized control group. Even a precisely estimated count within a cohort would describe that cohort's observed outcome; it would not, on its own, estimate a causal contrast between treatments.

Over-dispersion is a general issue when observed variation in count data exceeds what a chosen statistical model expects. In that situation, model-based uncertainty can be understated if the extra variation is ignored. The primary endpoint in this record is described as a count of participants, not as a count outcome analyzed with a stated distributional model. No model or dispersion assessment is reported in the registry record, so over-dispersion cannot be identified as a feature of this analysis. This general concept should not be mistaken for a reported study finding.

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("Cohort I: Recommended RefleXion FDG Dose (RRFD)")
n      <- c(6)
events <- c(6)
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  Cohort I: Recommended RefleXion FDG Dose (RRFD)  6  6  100.0  54.1  100.0  61.0  100.0  59.0  99.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures, spanning the primary endpoint and secondary measures across Cohort I and Cohort II. When a study examines multiple outcomes, the chance of at least one apparently notable result can increase if each is tested separately. Statistical approaches to multiplicity can address that issue, but the registry record does not report whether any adjustment, hierarchy, or prespecified outcome-testing strategy was used. No claim about multiplicity control can be made from the number of listed outcomes alone.

The record lists one analysis, but does not provide enough detail to identify which outcomes or participants that analysis covered, or what statistical methods were applied. The analysis populations, exclusions, and handling of missing outcome data are not reported in the registry record. In particular, the primary endpoint depends on receipt of 15 mCi, completion of imaging, and adequate target activity; the record does not state how participants with incomplete imaging or unavailable activity assessments were treated.

Missingness can affect interpretation when participants with unavailable results differ from those with observed results. General approaches include describing the extent and reasons for missing data and specifying how they are handled; no such details are reported in the registry record. The overall enrollment of 30 does not resolve this issue or establish the denominator for each endpoint.

The registry record also does not report whether analyses were intention-to-treat, per-protocol, or based on another defined population. Because the study was non-randomized and used sequential cohorts, these definitions would be important for understanding who contributed to each result. The available information does not support assumptions about exclusions, interim analyses, or prespecified statistical procedures.

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 record reports serious adverse events and other adverse events separately for the two cohorts. In Cohort I, 0 of 8 participants listed as at risk were affected by serious adverse events, and 5 of 8 were affected by other adverse events. In Cohort II, 0 of 9 participants listed as at risk were affected by serious adverse events, and 5 of 9 were affected by other adverse events. Deaths were recorded as 0 in both cohorts.

These figures are counts in the registry's listed risk groups. They are not a comparison of randomized treatment groups: the cohorts were sequential and had distinct study objectives. Zero reported serious events does not establish that the risk is absent; it describes the observed count in the listed groups. The record does not provide interval estimates or enough detail to assess the precision of these counts.

The registry record lists no serious adverse event terms. The specific terms for the other adverse events are not reported in the registry record information used for this analysis. The record lists toxicity related to FDG administrations as a Cohort II secondary outcome, but a numerical result for that outcome is not reported in the registry record. The counts should therefore be read as descriptive safety information, not as evidence that one dose, cohort, or treatment approach is safer than another.

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

BIOGUIDE-X was designed to assess technical performance and safety for biology-guided radiotherapy using the RefleXion Medical Radiotherapy System. Its primary endpoint focused on a prerequisite for planning: whether participants given 15 mCi FDG completed imaging and achieved adequate target activity concentration. The registry record states that escalation to 20 mCi was not required. This is relevant to the dose-finding objective, but does not replace the missing numerical result for the primary endpoint.

The record supports describing the study design, endpoint definition, and listed safety counts. It does not support stating how many participants met the primary endpoint, how precisely that result was estimated, or whether the prespecified performance criteria were met. The registry record also does not provide numerical results for the listed secondary outcomes in the information. Accordingly, the record does not establish the extent of imaging agreement, plan consistency, or physical dose-delivery performance.

The listed safety counts are limited observations from the cohort risk groups. They do not establish comparative safety because there was no randomized control group and the cohorts were not like-for-like arms. Nor do the counts establish that a particular event could not occur outside the observed participants.

More broadly, technical performance endpoints and clinical outcomes are distinct. A result showing that imaging or planning criteria were met would address those technical criteria; it would not, by itself, demonstrate a clinical benefit. The registry record's stated aims include performance and safety, but the primary endpoint is not a direct measure of patient benefit. The posted information also does not report a statistical plan sufficient to assess uncertainty, multiplicity, or missing-data effects. Interpretation should remain limited to the study objectives and data actually reported.

14. Why This Trial Matters Statistically

This study raises statistical questions that are common in early technical evaluations of medical devices. Its primary endpoint links a dose of FDG to completion of an imaging workflow and an adequacy criterion for treatment planning. That makes the definition of success, the number assessed, and the amount of uncertainty around the result central to interpretation. The registry record defines the endpoint but does not report its numerical count, leaving the key performance estimate unavailable.

The sequential cohort structure also matters. Cohort I and Cohort II were intended to answer different technical questions, and enrollment in the latter followed determination of the RRFD. Treating these cohorts as comparison arms would overlook their different purposes and the lack of randomization. Statistical descriptions should distinguish a within-cohort performance assessment from a causal comparison.

The study's range of outcome measures underscores why a clear analysis strategy matters. Imaging agreement, plan generation, physical phantom delivery, delivery concordance, localization, image concordance, and toxicity are not interchangeable endpoints. Their definitions, analysis populations, missing-data handling, and multiplicity approach all affect what conclusions can be drawn. The registry record lists these outcomes but does not report their numerical results or a detailed analysis plan.

Finally, the safety counts illustrate the limits of descriptive data. Counts without uncertainty estimates or a comparator can describe what was recorded in the assessed groups, but cannot quantify a comparative safety effect. Transparent reporting of denominators, endpoint results, and statistical methods is therefore important for readers evaluating the reach and precision of a technical study.

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 main limitation for interpretation is that the numerical primary endpoint result is not reported in the registry record. Although the endpoint criteria are described and the record states that dose escalation to 20 mCi was not required, the count meeting the criteria and its analysis denominator are unavailable. The precision of the primary performance estimate therefore cannot be assessed.

The registry record lists total enrollment of 30, but does not identify the number contributing to each outcome in the information available for this analysis. The adverse-event risk groups list 8 participants for Cohort I and 9 for Cohort II; those counts should not be treated as cohort enrollment totals for all endpoints. The record does not describe missing observations, exclusions, or analysis populations.

The non-randomized sequential design limits between-cohort interpretation. The cohorts had different objectives and were not a randomized, like-for-like comparison. The absence of masking is also recorded, while further details about outcome assessment procedures are not reported in the registry record. These features are relevant when interpreting subjective or technically assessed outcomes, without implying that any specific result was affected.

The registry record lists 12 outcome measures and one analysis but does not report the statistical methods, multiplicity approach, confidence intervals, or hypothesis tests. The listed safety counts have no reported interval estimates, and serious adverse event terms are not listed. Numerical results for the secondary endpoints are not reported in the registry record information used. These omissions prevent fuller evaluation of precision and outcome-by-outcome performance.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X) — NCT04788147.
• Registry record last updated 2023-10-31; status last verified 2023-10.
• Results first posted 2023-10-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

BIOGUIDE-X was a completed, non-randomized, sequential device study sponsored by RefleXion Medical. It listed enrollment of 30, no masking, and the RMRS IDE Device as the intervention. The study addressed performance and safety of biology-guided radiotherapy using the RefleXion Medical Radiotherapy System.

The primary endpoint was the number of participants receiving 15 mCi FDG who completed the RMRS imaging session and achieved adequate target activity concentration for planning. The registry record states that escalation to 20 mCi was not required, but does not report the endpoint count. Safety listings show no serious adverse events or deaths in the reported risk groups, with other adverse events affecting 5 of 8 participants in Cohort I and 5 of 9 in Cohort II.

The registry record does not report a detailed statistical plan, endpoint precision estimates, or numerical results for the listed secondary outcomes. The sequential cohorts should not be interpreted as randomized comparison arms.