A Pharmacodynamic Study to Evaluate Neutrophil Distribution Kinetics and Function Following Single-Dose RoActemra/Actemra (Tocilizumab) in Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Pharmacodynamic Study to Evaluate Neutrophil Distribution Kinetics and Function Following Single-Dose RoActemra/Actemra (Tocilizumab) in Healthy Volunteers (NCT01991990), a randomized phase 4 study. The primary outcome is Neutrophil Redistribution Analysis on Day 4 (Neutrophil Nadir).

2. Clinical Question

The study set out to explore the pharmacodynamic effects of tocilizumab on neutrophil redistribution, function and survival in healthy subjects. The primary endpoint focused on redistribution: after neutrophils were labelled and reinjected, whole-body profiling measured where the labelled cells were detected. The registry describes this assessment as a way to measure the effect of tocilizumab on the normal redistribution pattern and to assess neutrophil margination in its presence.

The endpoint was measured on Day 4, identified in the record as the neutrophil nadir. It was not a measure of symptoms, disease control or a clinical benefit in patients. The study enrolled healthy volunteers and investigated biological responses to a single dose. No numerical results for the primary endpoint, or a reported between-arm estimate, are available in the registry record, so the direction and precision of any group difference cannot be described.

3. Trial Design

This was a Phase IV, randomized, single-blind, parallel-arm study with an enrollment of 18 healthy volunteers. Participants were assigned to receive either tocilizumab or placebo. The registry record gives no arm descriptions beyond these treatment labels, and it does not report the randomization ratio or further details of how the allocation sequence was generated or concealed. The sponsor was Hoffmann-La Roche.

The study began in 2014-05, had primary completion in 2014-12, and is listed as completed. The planned treatment was a single intravenous dose of tocilizumab at 8 mg/kg over one hour on Day 0, or placebo. Neutrophil kinetics data were to be collected through Day 10. After the last study visit on Day 10, participants were to attend safety follow-up visits on Day 28 and Day 56.

For the Day 4 primary assessment, neutrophils were isolated from 100 mL of anticoagulated autologous venous blood, labelled with up to 2.5 MBq of 111In-tropolonate in autologous plasma, and reinjected. Participants rested for 45 minutes after reinjection to allow equilibrium between circulating and marginating neutrophil pools. Whole-body counts were then recorded using a dedicated, heavily shielded counter with two scintillation detectors. The record says counts were corrected for physical decay of 111In.

The registry lists 12 outcome measures and no analysis entries. That does not establish which analyses were actually conducted or whether results were analyzed outside the registry record. A detailed protocol, statistical analysis plan, sample-size justification and account of any interim analyses are not reported in the registry record. The study’s listed design therefore supports a description of its arms, timing and measurement procedures, but not a fuller reconstruction of its planned statistical comparisons.

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: The screening visit was up to 3 weeks before randomization to the first dose of study medication. Out of 23 screened participants; 5 participants discontinued (4=met exclusion criteria; 1=withdrew), 18 participants were included.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety analysis population: Includes all the participants who received the single dose of randomized study medication. One participant in the polymorphonuclear leukocyte (PMN)-high group was excluded due to external contamination affecting profiling data.

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: Includes all the randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Neutrophil Redistribution Analysis on Day 4 (Neutrophil Nadir), measured over Day 4.

The primary endpoint was neutrophil redistribution on Day 4, the time identified as the neutrophil nadir. It measured the distribution of radiolabelled neutrophils 45 minutes after reinjection, in blood, liver/spleen and pelvic bone marrow. Each compartment’s result was expressed as a percentage of total body counts. The endpoint was recorded as a mean with standard error.

The measurement was intended to characterize where neutrophils were located after circulating cells had been labelled and returned to the participant. The study description explains that a rest period followed reinjection to permit equilibrium between circulating and marginating pools. Whole-body profiling was used to assess the redistribution pattern, including margination, in the presence of tocilizumab.

As a continuous biological measure, the endpoint describes group-level distribution rather than a clinical event or a participant’s experience of illness. A mean can summarize the group’s measured distribution in a compartment, while the standard error describes the precision of that estimated mean. The standard error is not a description of the full spread of individual participants’ measurements.

The registry record does not report the endpoint’s mean values, standard errors, confidence intervals or a between-arm contrast. Because the endpoint covers several anatomical compartments, a result for one compartment alone would not necessarily describe the full redistribution pattern. The registry record does not provide the numerical profile needed to compare those compartments or to determine the magnitude or precision of any difference between the treatment groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record characterizes the primary endpoint as a continuous measure summarized by a mean and standard error. The sections below explain the statistical ideas relevant to such a measure and distinguish those general concepts from what can be established about this study. The record does not include numerical primary endpoint results or a detailed analysis plan.

What does a mean describe?

General statistical explanation: a mean combines participants’ measurements into a group-level summary. For this endpoint, the quantity being summarized is the percentage of total body counts attributed to a compartment. Means can help describe the typical measured distribution within an arm, but they do not show the range of individual observations or whether values are concentrated or widely spread. For a multi-compartment endpoint, interpreting one mean in isolation may leave out how the other compartments contribute to the overall profile.

The registry identifies blood, liver/spleen and pelvic bone marrow as the compartments assessed. It does not report the means for these compartments. Without those values, a reader cannot determine the observed distribution in either arm or describe how the measured profile differed between groups.

What does the standard error mean?

General statistical explanation: the standard error describes the precision of an estimated mean. It reflects uncertainty in the estimate rather than the variability of individual measurements. A standard error is therefore not interchangeable with a standard deviation, which describes dispersion among individual observations. The registry specifies standard error as the endpoint’s dispersion measure but does not include its numerical values.

Standard errors for two arms, by themselves, would not fully describe a treatment comparison. The estimated difference and its uncertainty are also relevant. A confidence interval is a range of values compatible with the data under a specified statistical procedure; its width communicates precision. No confidence interval for the primary comparison is reported in the registry record. No p-value for that comparison is reported either.

Why consider the compartments together?

General statistical explanation: a distribution across multiple compartments is naturally interpreted as a profile. A treatment-associated shift in one location may need to be considered alongside the measured shares in other locations. Because the endpoint expresses each compartment as a percentage of total body counts, these are components of a distribution rather than unrelated measurements. The registry record does not provide the compartment-specific results or describe a single summary across them. It would therefore be inappropriate to invent an aggregate result or reduce the endpoint to a single unreported comparison.

The endpoint description places the measurement 45 minutes after reinjection and notes a rest period intended to allow equilibrium between circulating and marginating pools. That procedure defines the time and context of the measurement. Statistical interpretation still depends on the recorded results, their variability, and the planned comparison; the biological measurement procedure alone does not determine whether an observed difference is precise or meaningful.

What can randomization contribute?

General statistical explanation: random allocation is intended to make treatment groups comparable, on average, with respect to factors present before treatment. This supports interpretation of a group contrast as related to assigned treatment when allocation and follow-up are implemented appropriately. The record identifies the study as randomized and parallel-arm, but does not report sequence generation, allocation concealment, or the randomization ratio. Those missing details prevent a more specific assessment of the allocation process.

Single blinding means that some party was blinded, but the registry record does not identify who. Blinding can reduce the influence of treatment knowledge on aspects of care, measurement or reporting, depending on who is blinded. The label alone does not establish that participants, investigators, endpoint assessors or analysts were all unaware of assignment. The record describes instrument-based profiling, but does not specify blinding arrangements for the profiling or analysis.

What do the planning assumptions mean?

General statistical explanation: sample-size calculations depend on assumptions about the target effect, variability, significance level, allocation and statistical method. A planning illustration asks what sample size might be needed under stated assumptions; it is not a result from participants and does not show the probability that this completed study detected an effect. The registry describes illustrations using a two-sided significance level of 0.05, equal allocation, a normal approximation, and target effects stated as fractions of an observed effect. It says these calculations are planning illustrations, not the trial’s own design justification.

The distinction matters because an illustrative calculation cannot replace a description of the actual study’s sample-size rationale, and it cannot supply a missing endpoint estimate. The registry does not report the study’s own sample-size justification. Nor does this record provide the primary outcome values needed to judge the observed treatment contrast. Such illustrations should not be read as observed power or as evidence that the study did or did not detect a difference.

What can the safety counts tell us?

General statistical explanation: event counts describe how many participants experienced an event within the recorded group. Counts should be read with their denominators, and not as precise comparative estimates. Uncertainty is especially important when group sizes are small. A count of zero serious events means none were recorded among the participants listed at risk; it does not by itself establish that the underlying event probability is zero. The registry does not provide confidence intervals or a comparative safety analysis for these counts.

Overall, the available statistical description is limited to the endpoint’s stated summary form, the study design labels, and the reported safety counts. The registry record does not report the analysis model, hypothesis tests, confidence intervals, covariate adjustment, or a detailed approach to repeated or multiple outcomes. Those methods cannot be inferred from the fact that the endpoint was continuous or from the trial’s randomized design.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint concerns several anatomical compartments, and the registry lists 12 outcome measures. Examining multiple outcomes or multiple components can raise a multiplicity question: when many comparisons are made, the chance of at least one apparently unusual result can increase. General statistical explanation: analysis plans may address this by defining a primary comparison in advance, adjusting inference, or emphasizing estimation and treating secondary findings as exploratory. The registry record does not report a multiplicity strategy or identify a correction method.

The record also does not report a detailed statistical analysis plan, analysis-specific participant counts for the primary endpoint, or a method for handling missing measurements. It says the safety analysis population included all participants who received a single dose of randomized study medication. One participant in the PMN-high group was excluded because external contamination affected profiling data. The registry does not clarify how that exclusion relates to each reported endpoint, whether any other measurements were unavailable, or whether sensitivity analyses were conducted.

The record lists no analysis entries. This does not establish that no statistical analyses were performed; it means analyses are not reported in the registry record. It also does not state whether there were interim analyses, whether the endpoint was analyzed according to randomized assignment, or whether any adjustment for baseline factors was made. These details are not reported in the registry record.

For those reasons, the primary endpoint cannot be reconstructed as a complete inferential comparison from the registry information. The stated mean and standard error format identifies how the measure was intended to be summarized, but not how multiplicity, missing data, exclusions or repeated measurements were handled in analysis.

11. 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 registry lists serious adverse events and adverse events other than serious events separately. For serious events, the recorded counts are 0 of 6 participants at risk in the placebo group and 0 of 12 in the tocilizumab group. For other adverse events, the recorded counts are 3 of 6 for placebo and 5 of 12 for tocilizumab. These are participant counts, not event totals, and they should be read with the corresponding group sizes.

General statistical explanation: a zero count means that no affected participants were recorded in that group during the period captured by the entry. It does not establish that the event could never occur, nor does it quantify the uncertainty around the underlying event rate. Likewise, the other-event counts alone do not establish a causal relationship or a reliable difference between groups. No confidence intervals or formal comparative safety analyses are reported in the registry record.

The deaths field is not reported in the registry record. The serious-event entries should not be interpreted as a complete account of all safety outcomes or as evidence about longer-term safety. The study description includes safety follow-up visits on Day 28 and Day 56, but the registry entries do not provide further event definitions or a fuller account of safety ascertainment. These figures are descriptive within this study and population.

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

This study addressed a pharmacodynamic question in healthy volunteers: how neutrophils were distributed among blood, liver/spleen and pelvic bone marrow after labelled cells were reinjected on Day 4, following a single dose of tocilizumab or placebo. The registry record gives considerable detail about the measurement procedure and specifies a mean with standard error as the endpoint summary. It does not report the numerical primary endpoint results.

As a result, the posted information does not show whether the measured distribution differed between the two arms, in which compartment any difference might have occurred, or how precise a comparison would be. It would be inaccurate to state that the treatment changed, or did not change, neutrophil redistribution based on this record alone. The missing result is central: design descriptions and measurement details cannot substitute for observed values and an estimated contrast.

The study also does not answer a clinical treatment question in patients. Participants were healthy volunteers, and the endpoint was a biological distribution measure rather than a clinical outcome. The record describes one dose and follow-up through Day 56, but it does not report results that would establish clinical benefit, or provide a basis for decisions about treatment. No medical advice follows from the information in this registry record.

The safety entries document no serious adverse events among the listed participants at risk and report other adverse events in both groups. They are descriptive counts, not a definitive comparative safety estimate. The deaths field is not reported in the registry record, and the record does not supply confidence intervals or a formal analysis of the event counts.

The responsible interpretation is therefore narrow. The record establishes the study’s randomized, single-blind, parallel-arm design, its healthy-volunteer population, treatment schedule and planned pharmacodynamic assessment. It also records limited adverse-event counts. It does not establish the magnitude or direction of a primary endpoint result, the precision of a treatment contrast, or the clinical implications of the biological question.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a carefully described measurement and a reportable result. The registry explains how labelled neutrophils were prepared, reinjected and profiled, and identifies the compartments used to describe redistribution. It also specifies the endpoint’s summary as a mean with standard error. Yet the numerical outcome values and comparison are not reported in the registry record. Without them, readers cannot assess the size, direction or precision of the primary finding.

The endpoint also illustrates why a biological distribution can require more than a single headline number. Blood, liver/spleen and pelvic bone marrow each contribute to the description, and the endpoint uses total body counts as the reference. A coherent interpretation would depend on the pattern across compartments. Statistical reporting should make clear what was estimated for each component, how the treatment groups were compared, and how uncertainty was represented. Those results and methods are not reported in the registry record.

The study’s safety counts show another statistical principle: raw counts must be read with their denominators and with appropriate caution. The record gives affected and at-risk counts, but not uncertainty intervals or comparative analyses. Such entries can describe what was recorded in this study without supporting broad conclusions about relative risk.

Finally, the sample-size assumptions are explicitly described as planning illustrations rather than the study’s own design justification. Keeping planning calculations separate from observed results prevents a common misinterpretation: a planning scenario is not evidence of observed power and does not resolve the absence of endpoint estimates. The registry record’s limitations make transparent reporting of the analysis plan, participant flow, outcome estimates and uncertainty especially important for interpreting this small pharmacodynamic study.

14. 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 numerical results for the primary endpoint are not reported in the registry record. The record does not give compartment-specific means or standard errors, a treatment contrast, confidence intervals or a p-value. Therefore, the primary pharmacodynamic question cannot be answered from the posted registry information, and the direction and precision of any difference cannot be assessed.

The endpoint involves multiple compartments, but the record does not state how these were combined or prioritized in analysis. Although 12 outcome measures are listed, their results and a multiplicity strategy are not reported. It is also unclear from the registry whether all planned outcome measurements were available for all participants or how missing values were handled. One participant in the PMN-high group was excluded because external contamination affected profiling data; the record does not describe sensitivity analyses or how this exclusion affected the estimates.

Further design and analysis details are not reported in the registry record. These include the randomization ratio and sequence-generation procedure, allocation concealment, who was blinded, the statistical analysis plan, any interim analyses, and the trial’s sample-size justification. The registry lists no analysis entries, which is not evidence that no analyses took place, but it leaves their methods and results undocumented in this record.

The safety information is also limited to counts. The registry does not provide confidence intervals, event definitions beyond the serious/non-serious distinction, or a comparative safety analysis. Deaths are not reported in the registry record. Finally, the study population was healthy volunteers and the intervention was a single dose; the record does not report clinical outcomes in patients. These constraints limit what can be inferred from the study description and posted safety entries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Pharmacodynamic Study to Evaluate Neutrophil Distribution Kinetics and Function Following Single-Dose RoActemra/Actemra (Tocilizumab) in Healthy Volunteers — NCT01991990.
• Registry record last updated 2015-11-11; status last verified 2015-10.
• Results first posted 2015-11-11.
• 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.

18. Record Summary

NCT01991990 is a completed, randomized, single-blind, parallel-arm Phase IV study sponsored by Hoffmann-La Roche. It enrolled 18 healthy volunteers and compared a single intravenous dose of tocilizumab, 8 mg/kg over one hour on Day 0, with placebo. The study began in 2014-05 and had primary completion in 2014-12.

The primary endpoint assessed radiolabelled neutrophil distribution on Day 4 in blood, liver/spleen and pelvic bone marrow, expressed as percentages of total body counts and summarized as a mean with standard error. The registry describes collection of neutrophil kinetics data through Day 10 and safety follow-up visits on Day 28 and Day 56. One participant in the PMN-high group was excluded from profiling because external contamination affected the data.

The registry reports serious adverse events in 0 of 6 placebo participants and 0 of 12 tocilizumab participants, and other adverse events in 3 of 6 and 5 of 12, respectively. Deaths are not reported in the registry record. Numerical primary endpoint results, detailed analysis methods and the study’s sample-size justification are not reported in the registry record.