Phase I Study Of The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Intravenously Administered Doses Of PF-04236921 In Patients With Rheumatoid Arthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I Study Of The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Intravenously Administered Doses Of PF-04236921 In Patients With Rheumatoid Arthritis (NCT00838565), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, parallel-group, placebo-controlled Phase 1 study in patients with rheumatoid arthritis receiving methotrexate. The official title describes patient and investigator blinding. The registry lists Pfizer as the sponsor and gives the study status as completed. Enrollment was 41. The study started on 2009-05-20, and primary completion was recorded as 2012-02-02.

The study summary describes monthly administration of PF-04236921 as three intravenous infusions. It also describes a dose-escalation approach: safety and tolerability at a low dose level were required before proceeding to successively higher dose levels. The posted safety groups include placebo and PF-04236921 at 1 mg, 10 mg, 30 mg, 100 mg, and 250 mg. The registry record does not report the allocation ratio, the number randomized to each group, or further operational details of escalation.

The primary safety outcome was the number of participants with treatment-emergent AEs and SAEs. The stated follow-up ran from baseline to 28 days after the last dose or until serum PF-04236921 concentrations were below the LLOQ, up to Day 624. The safety analysis set included participants who received at least 1 dose of study medication. The record lists 16 outcome measures and no analyses. It does not report a statistical analysis plan or an inferential comparison for the primary safety endpoint.

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: Safety analysis set included all participants who received at least 1 dose of study medication.

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: Safety analysis set included all participants who received at least 1 dose of study medication.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over Baseline up to 28 days after last dose of study medication or until serum PF-04236921 concentrations below the LLOQ (up to Day 624).

The primary endpoint is the number of participants with treatment-emergent adverse events and serious adverse events. It is a safety endpoint: it describes how many participants experienced events during treatment and the defined follow-up, rather than measuring improvement in rheumatoid arthritis. The registry defines an AE as an untoward medical occurrence in a participant who received study medication, regardless of whether a causal relationship was considered possible.

An SAE is an AE associated with outcomes such as death, initial or prolonged inpatient hospitalization, a life-threatening experience, persistent or significant disability or incapacity, or a congenital anomaly, or an event otherwise deemed significant. Treatment-emergent events were those absent before treatment or worsened relative to the pretreatment state during the specified period. The endpoint includes both serious and non-serious AEs.

Counting participants with events gives a direct description of how many people in each group were affected. It does not, on its own, describe event severity beyond the serious-event classification, the duration of an event, or whether a participant experienced more than one event. Nor does a group count establish that treatment caused an event. The registry record does not report a single summary comparison or statistical test for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Safety results are counts of participants with events in each treatment group. This is a descriptive way to present a binary outcome: a participant either met the endpoint definition or did not, based on the event information collected for the analysis. For this trial, the endpoint concerns treatment-emergent AEs and SAEs, with the safety analysis set defined as participants who received at least 1 dose. The registry’s group counts show the number of participants at risk and the number affected for serious events and other AEs.

What do participant counts tell us?

A count is readily interpretable, but its meaning depends on the group size and the event definition. For example, the serious-event results are reported as 0 of 9 for placebo, 0 of 6 at 1 mg, 0 of 6 at 10 mg, 2 of 6 at 30 mg, 1 of 6 at 100 mg, and 0 of 7 at 250 mg. Those figures describe the participants represented in the registry results. They do not show the uncertainty around the underlying risk, and a zero count does not establish that the event could never occur.

In general, a confidence interval expresses uncertainty around an estimate by giving a range of values compatible with the data and method. The registry record does not report confidence intervals for the primary safety results. A p-value, if reported, would address how compatible the data are with a specified statistical model or null hypothesis; it would not measure the probability that treatment caused an event. No p-value or hypothesis test for the primary endpoint is reported in the registry record.

Why does follow-up matter?

Participants were followed from baseline to 28 days after the last dose or until serum PF-04236921 concentrations were below the LLOQ, up to Day 624. A participant count does not incorporate differences in the time each person was observed or in the amount of study medication received. In general, if observation time differs substantially across groups, event counts alone may not be comparable as rates. Exposure-adjusted rates or time-to-event analyses can address some such differences, but the registry record does not report those analyses for the primary endpoint.

The treatment-emergent definition also matters. An event qualified if it was absent before treatment or worsened relative to the pretreatment state during the defined observation period. This makes the endpoint dependent on baseline status, event ascertainment, and the specified follow-up rules. The definition does not require that an event be judged caused by the study drug. Consequently, event counts are safety observations under treatment, rather than proof of drug-related harm or benefit.

What can a comparison establish?

Randomization is generally intended to support a fair comparison by distributing measured and unmeasured characteristics across groups on average. In a small Phase 1 study, chance differences can still occur. Blinding may reduce some influences on care or assessment, but the registry record does not describe how masking was maintained or whether it was assessed. These design features do not remove uncertainty from a small set of observed events.

A statistical comparison would need a defined estimand, a specified method, and a clear account of the analysis population. The record does not report a single comparison for the primary endpoint, and the outcome is explicitly not reduced to one comparison because it has several categories or time points. The absence of a reported comparison means the counts should not be converted into a claim of statistical significance or a treatment effect. It also means that the posted findings do not address whether any differences could be due to chance.

How should planning calculations be read?

The registry’s stated sample-size assumptions describe a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is described as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect. The record does not report the trial’s own sample-size justification. No planning calculation can substitute for an analysis of the actual safety data.

In general, over-dispersion means that outcomes vary more than a statistical model assumes. It can make standard errors too small if the model does not allow for that extra variability. This concept is relevant when a model is used for event counts, but the registry record does not report a count model or an over-dispersion analysis for this primary endpoint. The reported outcome is participant counts, and the registry does not state that a model-based analysis was performed.

These methods considerations place the results in their proper scope: they are group-specific safety counts gathered under a defined follow-up rule. Without reported confidence intervals, hypothesis tests, an adjusted analysis, or fuller information about exposure and missingness, the record supports description but not a precise inferential comparison.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint refers to treatment-emergent AEs and SAEs, while the registry record lists 16 outcome measures. The posted primary outcome has several categories or time points and is not reduced to a single comparison. The record does not report a statistical analysis plan specifying which comparisons were primary for inference, how multiple comparisons were handled, or whether any adjustment for multiplicity was made. Without those details, the event counts should be interpreted as descriptive rather than as a set of confirmatory tests.

The registry record defines the safety analysis population as participants who received at least 1 dose of study medication. It does not report how many randomized participants did not receive treatment, whether any participants were excluded from the safety analysis, or how missing safety information was handled. It also does not describe imputation, censoring rules beyond the stated follow-up, or sensitivity analyses for missing data.

In general, missing data can affect a safety summary if participants with incomplete observation differ from those with complete observation. The direction and size of any such effect depend on why information is missing and what events occurred. The record does not report enough information to assess this issue. Similarly, because the endpoint follow-up could continue to 28 days after the last dose or until serum concentrations were below the LLOQ, up to Day 624, group counts alone do not show whether observation time was comparable.

No interim analyses or other prespecified monitoring procedures are reported in the registry record. The statistical analysis plan is not reported in the registry record. These gaps prevent a detailed assessment of the analysis decisions behind the posted safety summaries.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chest pain (16.7%), abscess limb (16.7%), pneumonia (16.7%), road traffic accident (16.7%), plantar fasciitis (16.7%).

The serious adverse event figures count participants with at least one SAE in each listed group: 0 of 9 for placebo, 0 of 6 for PF-04236921 1 mg, 0 of 6 for 10 mg, 2 of 6 for 30 mg, 1 of 6 for 100 mg, and 0 of 7 for 250 mg. These are participant counts, not counts of all serious events. A participant could experience more than one event, but the registry’s primary outcome is expressed as the number of participants with events.

The separate figures for other AEs are 9 of 9, 4 of 6, 4 of 6, 6 of 6, 6 of 6, and 5 of 7 across placebo and the listed dose groups, respectively. The registry record’s definition includes AEs regardless of whether a causal relationship was considered possible. Therefore, these summaries do not establish that study medication caused any event.

Each listed serious-event term is reported as 16.7%. The record does not provide enough information in this summary to determine the denominator behind those percentages or to assign every term to a treatment group. Death counts are not reported in the registry record. None of these descriptive results, by themselves, establishes a statistically reliable difference between treatment groups.

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

The results describe adverse events recorded in a randomized, double-blind, placebo-controlled Phase 1 study of PF-04236921 in patients with rheumatoid arthritis receiving methotrexate. They provide group-specific counts of participants with serious adverse events and other adverse events over the defined safety follow-up. The counts show that serious events were recorded in the 30 mg and 100 mg groups, while the other listed groups had no participants with an SAE in the posted results. The other-AE counts are also reported for every group.

These findings do not establish that PF-04236921 caused an event, nor do they establish that the treatment did or did not affect the risk of events. The endpoint definition includes events without regard to the possibility of a causal relationship. In addition, small group counts are subject to substantial uncertainty, and the registry does not report confidence intervals, p-values, or a single inferential comparison for the primary endpoint.

The absence of a reported SAE in a group is not evidence that no risk exists. Likewise, an SAE recorded in a treatment group does not by itself establish a treatment-related safety signal. The event terms and percentages are descriptive listings, not a comparative estimate of risk. The registry record does not report deaths in the posted adverse-event information; that omission should not be read as a confirmed absence of deaths.

The trial was a Phase 1 study and its stated focus was safety and tolerability alongside pharmacokinetics and pharmacodynamics. The registry summary does not establish a treatment effect on rheumatoid arthritis outcomes. No advice about an individual’s treatment can be drawn from these group-level safety summaries. Their appropriate interpretation is limited to what was recorded in this study and how the registry describes the analysis.

13. Why This Trial Matters Statistically

This study illustrates a basic challenge in early-phase safety research: counts of participants with events are easy to understand, but sparse events and small groups limit the precision of comparisons. The serious adverse event results range from no recorded participants with an SAE in several groups to 2 of 6 in the 30 mg group and 1 of 6 in the 100 mg group. Those observations are important to describe, but they cannot alone establish a stable risk estimate or a causal relationship.

The trial also shows why outcome definitions and follow-up rules matter. The primary endpoint distinguishes treatment-emergent events from events that were already present or did not worsen, and it includes both serious and non-serious AEs. Follow-up could extend to 28 days after the last dose or until serum concentrations were below the LLOQ, up to Day 624. This context is necessary to understand what the counts represent.

Statistically, a safety summary is not automatically a treatment comparison. The registry lists outcome measures but does not report a single primary-endpoint comparison, an inferential analysis, or a statistical analysis plan. A reader therefore needs to distinguish observed counts from evidence about a difference between groups. The trial is a useful example of why analysis populations, event definitions, exposure duration, uncertainty, and multiplicity should be reported alongside descriptive safety results.

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 registry record reports enrollment of 41 but does not provide a full account of how many participants were randomized, treated, or followed in each group beyond the denominators in the posted safety results. The safety population is defined as participants who received at least 1 dose, but the record does not describe exclusions or incomplete safety follow-up. It also does not report participant-level exposure or follow-up duration by group.

The primary endpoint is reported through event categories and time points rather than a single treatment comparison. The registry record does not provide confidence intervals, p-values, adjusted effect estimates, or the analysis plan. It does not report whether multiple comparisons were addressed, whether interim analyses took place, or how missing data were handled. Sample-size justification for the trial is not reported in the registry record.

The serious-event terms are listed with percentages, but the registry information available for these results does not identify the denominator for those percentages or provide a treatment-group breakdown for each term. Death counts are not reported in the registry record. The safety counts should therefore be read as descriptive results, not as a complete account of all possible safety analyses.

The study summary describes monthly dosing as three intravenous infusions and describes progression to higher dose levels after safety and tolerability at a low dose level. Further details about dose escalation, randomization, masking procedures, and the timing of individual events are not reported in the registry record. These limitations constrain interpretation of differences among groups and the extent to which findings can be generalized beyond this trial.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I Study Of The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Intravenously Administered Doses Of PF-04236921 In Patients With Rheumatoid Arthritis — NCT00838565.
• Registry record last updated 2018-11-02; status last verified 2018-03.
• Results first posted 2018-11-02.
• 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

NCT00838565 is a completed, randomized, double-blind, parallel-group, placebo-controlled Phase 1 study sponsored by Pfizer. It enrolled 41 patients with rheumatoid arthritis receiving methotrexate. The study evaluated intravenous PF-04236921 across dose groups, with placebo as comparator; the posted safety groups include 1 mg, 10 mg, 30 mg, 100 mg, and 250 mg.

The primary outcome counted participants with treatment-emergent AEs and SAEs during follow-up from baseline to 28 days after the last dose or until serum concentrations were below the LLOQ, up to Day 624. The registry reports group counts for serious events and other AEs, but does not report a single inferential comparison, confidence intervals, or a statistical analysis plan. The posted results are best read as descriptive safety findings, with uncertainty and limits on causal interpretation.