Evaluating Safety of Escalating Doses of Tilmanocept by IV Injection and SPECT Imaging in Subjects With and Without RA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluating Safety of Escalating Doses of Tilmanocept by IV Injection and SPECT Imaging in Subjects With and Without RA (NCT02865434), a non-randomized phase 1, phase 2 study. The primary outcome is Incidence of Adverse Drug Reaction.

2. Clinical Question

The central question is about safety and the ability of Tc 99m tilmanocept to localize in skeletal joints, rather than a randomized test of clinical benefit. The study enrolled people with active RA as well as healthy controls, and the intervention included intravenous injection followed by imaging. Its planned secondary outcomes include subject-level localization, localization in RA-identified joints, concordance, localization intensity, localization outside RA areas, and pharmacokinetic measures.

The registry record describes escalating doses across RA groups, with further groups receiving the MTD. It does not report the MTD amount or explain how that dose was selected. The non-randomized structure means that differences between groups cannot be interpreted as clean causal effects of dose or disease status: assignment was not described as random, and the groups do not constitute a like-for-like control comparison.

3. Trial Design

This was a completed, prospective, open-label, multicenter, dose-escalation study in Phase 1 and Phase 2. The registry record lists an enrollment of 39. It describes a parallel model and non-randomized allocation, with no masking. The study started in 2017-01 and had primary completion in 2018-06.

Nine groups of participants with RA are described. Groups 1 through 3 received 10 mCi of Tc99m with 50 µg, 200 µg, or 400 µg of tilmanocept. Groups 4 through 6 received 5 mCi with those same listed tilmanocept amounts, and Groups 7 through 9 received 1 mCi with those amounts. These groups underwent SPECT imaging at 60 minutes and 180 minutes post-injection.

Group 10 comprised healthy controls and Group 11 comprised participants with RA. Both are described as receiving tilmanocept at the MTD and undergoing whole-body planar SPECT imaging at 15 minutes, 60 minutes, 180 minutes, and 18-20 hours post-injection. The MTD dose itself is not reported in the registry record. Although blood collection for pharmacokinetic testing is listed among the procedures, the schedule and analysis details are not reported in the registry record.

Because the study was open-label and non-randomized, participants and study personnel were not masked, and group assignment was not random. The record does not report the allocation process, the rationale for the group sizes, or a sample-size justification. The intervention and imaging schedule describe an exploratory safety and localization evaluation; they do not establish a randomized comparison of treatment effects.

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.

Only the first 6 of 11 groups are shown.

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.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Adverse Drug Reaction, measured over From Enrollment to termination, up to 53 days.

The primary endpoint is the incidence of adverse drug reaction, expressed as the number of participants who experienced pharmacologic activity or an adverse drug reaction in each dose group. The timeframe is from enrollment to termination, up to 53 days. A participant count is a direct way to describe how many people in each group had a recorded event during that period.

For a dose-escalation safety study, this kind of endpoint helps describe whether events were observed as exposure varied. It is an event-count measure, not a measure of event severity alone, and the registry description combines pharmacologic activity with adverse drug reactions. Interpretation therefore depends on the specific event definitions and reporting rules, which are not reported in the registry record.

The posted safety summary distinguishes serious adverse events from other adverse events. Those categories provide useful context, but the counts do not by themselves establish whether an event was caused by the intervention. The registry record does not report a formal causal-attribution method or a separate numerical result for the primary endpoint beyond the safety counts. The endpoint also does not answer the planned imaging and pharmacokinetic questions; those outcomes require their own reported results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General explanation: a dose-escalation safety study examines observations across groups assigned different exposure levels. Its purpose and design differ from a randomized efficacy comparison. In a randomized study, random assignment is used to make groups more comparable on average. In this trial, allocation was non-randomized, so group differences may reflect factors other than the dose or radioactivity. The registry record does not describe how participants were assigned to groups.

What does a participant count represent?

The primary endpoint is defined as the number of participants experiencing pharmacologic activity or an adverse drug reaction in each dose group. A count is straightforward to interpret as an observed number of people, but it is not a complete measure of risk on its own. It needs a denominator, a consistent observation period, and clear event definitions. The safety summary gives at-risk and affected counts by group and frames the endpoint from enrollment to termination, up to 53 days. The registry record does not report further details about event adjudication, coding, or how pharmacologic activity was distinguished from an adverse drug reaction.

General explanation: uncertainty matters even when a count is exact. A confidence interval would express a range of values compatible with the observed data under a specified statistical model. No confidence intervals for the adverse-event counts are reported in the registry record. With small groups, an observed zero is compatible with uncertainty about the underlying event frequency; it should not be treated as proof of absence.

Why is this not a randomized comparison?

Randomization can reduce systematic differences between groups, while masking can reduce the influence of expectations on care, assessment, or reporting. This trial was non-randomized and had no masking. As a result, the adverse-event counts can describe what was recorded in each group but do not isolate a causal effect of dose, radioactivity, or RA status. The record itself identifies the arms as not being a like-for-like control comparison. No adjusted comparison or inferential analysis is listed.

The study is described as parallel, meaning the record identifies separate groups rather than a crossover comparison in which the same participant receives multiple conditions. The group descriptions specify different combinations of tilmanocept amount and radioactivity for participants with RA. Healthy controls and an additional RA group received tilmanocept at the MTD, with the amount not reported in the registry record. The record does not report the method used to select the MTD or the basis for dose escalation.

How should the imaging outcomes be understood?

The stated imaging schedule uses SPECT at 60 minutes and 180 minutes post-injection for the first nine RA groups. The two later groups are described with whole-body planar SPECT imaging at 15 minutes, 60 minutes, 180 minutes, and 18-20 hours post-injection. Listed secondary outcomes include per-subject localization, localization in RA-identified joints, concordance, localization intensity, and localization outside RA areas. These outcomes concern where and how strongly imaging signal is observed; they are distinct from the primary safety endpoint. Numerical results, definitions of a positive localization, and analysis methods for these outcomes are not reported in the registry record.

General explanation: repeated imaging times can describe how an imaging signal changes over time, while a localization rate can summarize how often a specified location is identified. Interpretation depends on the definition of a localized joint, the method used to read images, and whether readers were masked. Those details are not reported in the registry record, so the listed outcomes alone do not establish how these measures were calculated.

What do the pharmacokinetic measures describe?

The record lists maximum observed concentration (Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve from hour 0 to the last measurable concentration (AUC0-t). In general, Cmax describes the highest measured concentration, Tmax describes when that maximum is reached, and AUC summarizes concentration over time across the specified interval. These are descriptive pharmacokinetic concepts, not clinical benefit measures. The registry record does not report numerical results, sampling details beyond the listed blood collection before injection, or a statistical analysis plan for these outcomes.

What can the planning illustrations say?

General explanation: a sample-size planning illustration asks how many participants might be needed under specified assumptions to detect an effect of a chosen size. It is not an estimate of the trial's observed power and does not change what was actually enrolled. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. The registry record does not report that these assumptions were the trial's own design rationale or sample-size justification. No numerical planning result needs to be interpreted as a trial finding.

The registry record lists no analyses. It does not report a prespecified statistical plan, treatment of missing outcome data, interim analyses, multiplicity adjustment, or analysis populations. These omissions limit assessment of how outcomes would have been selected and tested. General explanation: prespecification helps clarify which comparisons and outcomes were intended to drive interpretation; adjustment for multiple testing may be relevant when many outcomes are evaluated. Without those details and the outcome results, the listed secondary measures should be regarded as planned questions rather than demonstrated findings.

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("Group 1 (RA)", "Group 2 (RA)", "Group 3 (RA)", "Group 4 (RA)", "Group 5 (RA)", "Group 6 (RA)")
n      <- c(3, 3, 3, 3, 3, 3)
events <- c(3, 3, 3, 3, 3, 3)
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  Group 1 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Group 2 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Group 3 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Group 4 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Group 5 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Group 6 (RA)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 13 outcome measures, including the primary safety endpoint and secondary localization, concordance, intensity, and pharmacokinetic outcomes. It lists no analyses. A statistical analysis plan, including any hierarchy of outcomes or planned comparisons, is not reported in the registry record. Nor is any multiplicity adjustment reported.

General explanation: when many outcomes or comparisons are tested, the chance of finding at least one apparently unusual result can increase. A prespecified outcome hierarchy or multiplicity adjustment can help make interpretation more disciplined. Here, the record does not give enough analysis detail to determine whether such methods were planned or used. Since numerical results for the listed secondary outcomes are not reported, their findings cannot be assessed.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not say how missing images, missed visits, incomplete blood sampling, or participants without evaluable outcome measurements were handled. It does not identify an intention-to-treat, per-protocol, or safety population. The safety summary gives at-risk counts for each group, but these alone do not describe participant flow or explain whether all enrolled participants contributed to each outcome.

These gaps matter because outcome availability and analysis choices can affect the interpretation of a small, non-randomized study. They do not establish that data were missing or that analyses were inappropriate; they mean that the registry record does not report the information needed to evaluate those issues.

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 serious adverse-event counts are 0 in every listed group. Groups 1 through 9 each had 3 participants at risk, and Groups 10 and 11 each had 6 participants at risk. The death count was 0 in every group. These observations describe the participants included in the safety summary during the stated follow-up period; they do not rule out the possibility of serious events in a larger population or over a different observation period.

Other adverse-event counts were 3 in Group 1, 1 in Group 6, 1 in Group 8, 2 in Group 10, and 1 in Group 11. The count was 0 in Groups 2, 3, 4, 5, 7, and 9. These counts should not be combined into a causal comparison across groups. The study was non-randomized, group sizes were limited, and the registry record does not report a like-for-like control comparison or a formal method for attributing events to the intervention.

General explanation: serious and non-serious adverse events are different reporting categories, and a count in one category should not be interpreted as a severity scale for all events. The registry record does not provide event descriptions for these counts. The zero serious-event counts are therefore a limited descriptive safety observation, not proof that the intervention is free of risk.

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

The posted results support a narrow descriptive statement: no serious adverse events or deaths were recorded in the listed groups, while other adverse events were recorded in some groups. The counts are reported against the number at risk in each group. They characterize the observed safety summary; they do not estimate a comparative effect between randomized groups, because the study was non-randomized and the arms are not a like-for-like control comparison.

The trial was designed to evaluate safety, pharmacokinetics, dosimetry, and localization to skeletal joints in participants with and without active RA. The registry record describes SPECT imaging and lists localization and pharmacokinetic outcomes, but does not report numerical results for those outcomes. Therefore, the safety counts cannot be used to conclude that joint localization occurred or to characterize the imaging signal, drug concentration, or dosimetry.

Nor do the posted counts establish whether an adverse event was caused by Tc99m-tilmanocept. The record does not report a formal causality assessment, detailed event descriptions, or an analysis comparing dose groups. Non-random assignment, open-label conduct, and the small group sizes limit interpretation of any apparent difference in event counts. An observed count of zero does not establish zero underlying risk.

General explanation: statistical evidence has to be interpreted in relation to the question a study was designed to answer, the design used, and the precision of the estimates. Here, the posted safety information is descriptive. The registry record does not report confidence intervals, a formal inferential analysis, or results for the secondary imaging and pharmacokinetic questions. The findings do not demonstrate clinical benefit, and they do not provide a basis for treatment decisions.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of why early dose-escalation studies need to be read differently from randomized comparative trials. The groups were organized around differing amounts of tilmanocept and radioactivity, with additional RA and healthy-control groups at the MTD. That structure can support descriptive observation across exposures, but non-random allocation does not ensure that groups are comparable in other respects.

The endpoint is a participant count for pharmacologic activity or adverse drug reaction, and the safety summary separately reports serious and other adverse events. Such counts are easy to communicate, yet their interpretation depends on group size, event definitions, observation time, and uncertainty. The available groups are small, and no confidence intervals or formal analyses are reported in the registry record. This illustrates why a zero count should not be treated as evidence that the underlying event risk is absent.

The protocol also links safety assessment with imaging, pharmacokinetic, and dosimetry questions. These outcomes are conceptually distinct: event counts describe safety observations, imaging outcomes concern localization, and pharmacokinetic measures describe concentrations over time. The registry record lists these questions but does not report numerical results for the secondary outcomes. Separating planned measurement from reported evidence is essential to a careful statistical reading.

Finally, the record lists no analyses and does not report the statistical plan, missing-data approach, analysis populations, multiplicity handling, or sample-size justification. These are not minor details when evaluating how results were selected and how precisely they answer a question. The trial matters statistically because it shows both the value and the limits of descriptive evidence in an early, non-randomized 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.

Interpretation is constrained by the non-randomized allocation and lack of masking. Group differences may reflect factors other than dose, radioactivity, or RA status, and event reporting may be influenced by the open-label design. The registry record explicitly cautions that the arms are not a like-for-like control comparison.

The safety groups were limited in size: the first nine groups each had 3 participants at risk, and the final two groups each had 6. Such counts provide limited precision, especially for uncommon events. No confidence intervals or formal between-group estimates are reported. The registry record also does not report detailed adverse-event descriptions, event definitions, or a causal-attribution procedure.

The MTD amount is not reported in the registry record, and the method or criteria used to select it are also not reported. The record does not describe the group assignment process, sample-size justification, interim analyses, statistical plan, analysis populations, multiplicity handling, or missing-data methods. Participant characteristics and detailed eligibility criteria are not reported.

Although numerous imaging and pharmacokinetic outcomes are listed, numerical results and analysis methods for these outcomes are not reported in the registry record. The record therefore does not allow assessment of localization findings, pharmacokinetic estimates, or dosimetry results. The safety counts alone cannot fill those gaps or establish efficacy.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluating Safety of Escalating Doses of Tilmanocept by IV Injection and SPECT Imaging in Subjects With and Without RA — NCT02865434.
• Registry record last updated 2021-08-12; status last verified 2021-08.
• Results first posted 2021-08-12.
• 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

NCT02865434 is a completed Phase 1/Phase 2, prospective, open-label, multicenter, non-randomized, parallel dose-escalation study sponsored by Navidea Biopharmaceuticals. It enrolled 39 participants with active RA and healthy controls. The study evaluated intravenous Tc99m-tilmanocept, SPECT imaging, safety, pharmacokinetics, and dosimetry.

The primary endpoint was the number of participants with pharmacologic activity or an adverse drug reaction in each dose group, from enrollment to termination, up to 53 days. The safety record reports no serious adverse events and no deaths in the listed groups, with other adverse events recorded in some groups. The groups are not a like-for-like control comparison.

Secondary outcomes include localization, concordance, localization intensity, and pharmacokinetic measures. Their numerical results are not reported in the registry record. The record lists 13 outcome measures and no analyses; details of the statistical plan, missing-data handling, and analysis populations are not reported in the registry record.