Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis (NCT00771030), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events.

2. Clinical Question

3. Trial Design

This randomized, quadruple-masked study was listed as Phase 1 and Phase 2, and the summary describes it as Phase 1b/2a. Its model was sequential, with dose escalation in Part A to assess safety and tolerability, followed by dose expansion in Part B to assess clinical efficacy at the highest tolerated dose level from Part A. The registry does not report the operational rules for moving between parts or selecting that dose.

The study enrolled 40 participants. It included subcutaneous brodalumab cohorts at 50 mg, 140 mg, and 210 mg, each dosed once every 2 weeks for six doses, and intravenous cohorts at 420 mg and 700 mg, each dosed once every 4 weeks for two doses. Route-matched placebo groups were listed for the subcutaneous and intravenous cohorts. The design therefore involved multiple dose and route groups rather than one simple two-arm comparison.

The listed primary outcome was the number of participants with treatment-emergent adverse events through week 19. Secondary outcomes covered brodalumab pharmacokinetics after subcutaneous and intravenous dosing, including maximum concentration, time to maximum concentration, area under the concentration-time curve, and accumulation ratio. The registry reports 12 outcome measures and 0 analyses. It does not report the allocation ratio, the sequence or timing of cohort enrollment, or a detailed statistical analysis plan.

The study started on 2008-10-27, reached primary completion on 2010-05-25, and is listed as completed. Amgen is named as sponsor.

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: Within each cohort participants were randomized 3:1 to receive ascending doses of brodalumab or placebo subcutaneously (cohorts 1 to 3) or intravenously (cohorts 5 and 6). Cohort 4 was designed to be used in the dose expansion part of the study, however, this cohort was not enrolled because experimental endpoints would be achieved during a separate phase II study.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received at least 1 dose of study drug (placebo or brodalumab).

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: All enrolled participants

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events, measured over From first dose of study drug up to end of study (week 19)..

The primary endpoint was the number of participants with treatment-emergent adverse events, reported as a count of participants. The timeframe ran from the first dose of study drug through the end of study at week 19. The endpoint population included randomized participants who received at least 1 dose of placebo or brodalumab.

An adverse event was defined broadly as an untoward medical occurrence in a participant administered a pharmaceutical product. The definition does not require that the event be caused by the treatment; it includes an occurrence such as a sign, symptom, diagnosis, or worsening of a pre-existing medical condition. This distinction matters: an event recorded during treatment is not, by itself, evidence that the study drug caused it.

The registry also defined serious adverse events by specified outcomes or severity, including fatal or life-threatening events, events requiring inpatient hospitalization or prolonging existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, and other significant medical hazards. Seriousness is a regulatory classification and is distinct from whether an event is considered related to treatment.

Counting participants with events is a direct way to describe how many participants experienced events during the stated observation period. It does not convey the number of separate episodes per participant, the duration of events, or a causal treatment effect. Those details and a formal comparison analysis are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a count endpoint: the number of participants with treatment-emergent adverse events. A count endpoint records how many people met the event definition, rather than measuring a continuous quantity such as a laboratory value. The outcome is framed at the participant level, so it does not necessarily represent the total number of event episodes. A participant with several events may still contribute as one participant with an event, depending on the outcome’s counting rules; detailed rules for handling multiple events are not reported in the registry record.

What does a count describe?

A count is easiest to interpret alongside the number of participants at risk. The registry lists both for serious events and other adverse events in each group. These figures describe the observed experience in the specified cohorts during follow-up. They do not automatically establish that one group has a higher underlying risk than another. In small groups, counts are sensitive to the experience of individual participants, and uncertainty around any population-level interpretation would be substantial.

General statistical explanation: an estimate describes a quantity in the observed data, while an uncertainty interval describes a range of values compatible with the data under a specified statistical model. The registry record does not report confidence intervals for this primary endpoint, nor does it report a modeled effect estimate. No interval or comparative effect should be inferred from the counts alone.

Why do the cohort structures matter?

The study had a sequential model with dose escalation and dose expansion, and it used multiple brodalumab doses, routes, and placebo groups. A simple comparison would require a clearly defined contrast, such as which brodalumab group is being compared with which placebo group and for what estimand. The registry does not report a single primary comparison or analysis for this endpoint. Combining groups or selecting a comparison would introduce an analytical choice not described in the record, so the counts are best kept in their listed groups.

General statistical explanation: a randomized comparison can help distinguish treatment-group differences from some sources of confounding, but its interpretation depends on the planned comparison, the participants included, and how outcomes are analyzed. Randomization is listed, but details such as the allocation ratio and the specific analysis model are not reported. The record also does not explain whether comparisons were adjusted for dose, route, cohort, or other factors.

What can p-values and confidence intervals add?

General statistical explanation: a p-value assesses how compatible the observed data are with a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. A confidence interval conveys uncertainty about an estimated effect under a model. Neither a p-value nor a confidence interval is reported for the primary adverse-event outcome. The registry lists 0 analyses, so no inferential result for this outcome is available to interpret.

The sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a fraction of the observed effect. These are planning illustrations, not the trial’s own design justification and not observed power. The registry does not report a sample-size justification, and no illustration values are included in the registry record for discussion. In addition, a two-arm planning setup does not itself specify how to analyze this sequential, multi-cohort trial.

How should multiplicity be considered?

Multiple outcomes, doses, routes, and cohort comparisons create the possibility of examining several results. General statistical explanation: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan accounts for multiplicity. The registry lists 12 outcome measures but does not report an adjustment strategy, hierarchy of hypotheses, or a detailed statistical plan. It is not possible to determine how multiplicity was handled.

The registry record does not report interim analyses, missing-data methods, a model for the adverse-event endpoint, or a detailed definition of the analysis populations beyond the primary endpoint population. It would be inappropriate to assume particular procedures. The available endpoint counts support a descriptive account, while formal inference and the analysis decisions behind it remain unspecified.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, including the primary adverse-event count and secondary pharmacokinetic measures. It also describes multiple doses, two routes of administration, and several cohorts. These features create multiple possible outcome and group comparisons. The registry record does not report a hierarchy of hypotheses, a multiplicity adjustment, or a detailed statistical analysis plan. It is therefore not possible to determine whether or how the study controlled the chance of false-positive findings across multiple analyses.

The primary endpoint population is defined as all randomized participants who received at least 1 dose of study drug. The record does not describe how participants who were randomized but did not receive a dose were handled in other analyses, or how missing outcome information was addressed. It also does not report the amount or pattern of missing data. The listed at-risk counts give the group denominators for the adverse-event figures, but they do not explain whether all participants had complete follow-up through week 19.

The registry reports 0 analyses for the outcome set and does not specify an inferential model, interim analyses, or a missing-data method. It is not possible to infer that any particular approach was used. The reported counts can be described as posted, but they do not establish how incomplete observations, repeated events, or potential differences in follow-up were handled analytically.

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: gastrooesophageal reflux disease (16.7%), non-cardiac chest pain (16.7%), complicated migraine (16.7%).

The serious adverse-event figures are participant counts within the listed groups. One participant was reported with a serious adverse event in Placebo SC (Cohorts 1-3), and one in Brodalumab 420 mg IV (Cohort 5). The serious-event count was 0 in each of the other listed groups: Placebo IV (Cohorts 5-6), Brodalumab 50 mg SC (Cohort 1), Brodalumab 140 mg SC (Cohort 2), Brodalumab 210 mg SC (Cohort 3), and Brodalumab 700 mg IV (Cohort 6).

The listed serious-event terms were gastrooesophageal reflux disease, non-cardiac chest pain, and complicated migraine, each reported as 16.7%. The registry does not specify in this outcome listing the participant-level mapping of those terms or whether terms refer to distinct participants. The terms and percentages should therefore be read as registry descriptions, not as evidence that an event was caused by a study treatment.

Seriousness is based on the registry definition, which includes specified outcomes such as hospitalization or life-threatening events and other significant medical hazards. Seriousness does not establish treatment causality. The record lists no death counts for these groups, so deaths are not reported in the registry record. The small group sizes and absence of a formal comparative analysis mean these counts should remain descriptive rather than being treated as a precise estimate of relative safety.

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

The results establish what the registry reported for the treated participants in the listed cohorts: counts of participants with serious and other adverse events during the stated observation period. The primary outcome was assessed from the first dose through the end of study at week 19, and the primary population included randomized participants who received at least 1 dose of study drug. The counts provide a compact description of events recorded in those groups.

They do not establish that an event was caused by brodalumab or placebo. The adverse-event definition explicitly includes occurrences that do not necessarily have a causal relationship with treatment. Nor do the counts by themselves show whether one treatment is safer than another. The registry does not report a formal comparative analysis, an effect estimate, a confidence interval, or a p-value for the primary outcome.

The counts also do not show the total burden of repeated events, their duration, or their severity beyond the separate serious-event classification. A participant count is not the same as an episode count. The posted information does not provide enough detail to resolve how multiple events in one participant were represented in the outcome summaries.

The study included pharmacokinetic and pharmacodynamic objectives, and Part B was described as an assessment of clinical efficacy at the highest tolerated dose from Part A. However, the relevant efficacy results and detailed pharmacokinetic results are not reported in the registry record details. The existence of those objectives should not be mistaken for evidence of a particular outcome.

Finally, a completed study and a set of posted counts do not answer every question about generalizability or precision. The cohorts were small, and the registry does not report the statistical plan, missing-data approach, or a single treatment contrast. The appropriate interpretation is limited to the descriptive adverse-event information and the design features expressly recorded.

13. Why This Trial Matters Statistically

This trial is statistically notable for its sequential, multi-cohort structure. It combined dose escalation intended to assess safety and tolerability with dose expansion intended to assess clinical efficacy at the highest tolerated dose from Part A. The interventions varied in dose and route, while placebo was also given through route-specific cohorts. This makes the analysis question more complex than a single comparison between one treatment group and one control group.

The primary outcome is a participant count, and the registry reports it across groups with small denominators. Counts are transparent and useful for describing what occurred in these cohorts, but they offer limited precision for drawing conclusions about broader populations. Their interpretation also depends on the event definition, follow-up, and the population included in each analysis.

The record lists 12 outcome measures but 0 analyses. That gap is important: outcome definitions identify what was intended to be measured, while analysis results and methods explain how comparisons were made and what uncertainty surrounds them. Without a reported comparative estimate or analysis plan, readers cannot assess whether any observed differences were prespecified, adjusted for multiple comparisons, or modeled across dose and route.

The study also illustrates the distinction between safety monitoring and evidence of causation. Treatment-emergent events are collected during exposure, but the definition does not require a causal link. Describing event counts carefully, without treating them as proof for or against a treatment effect, is essential when evidence is limited to small cohort counts.

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 provides limited information for evaluating the primary outcome beyond the group counts. It does not report a detailed statistical analysis plan, a model, an effect estimate, confidence intervals, or p-values for the adverse-event endpoint. The reported counts therefore support description but not a formal assessment of comparative uncertainty.

The study included several doses, routes, and cohorts, with a sequential design. The registry does not report a single primary treatment contrast, allocation ratio, or detailed cohort progression rules. It is not possible to determine how the investigators selected comparisons or whether they pooled any groups. The record also does not report how multiplicity was addressed across outcomes or potential comparisons.

Small group sizes limit the precision of descriptive comparisons. The registry’s at-risk counts range from 4 to 6 participants across the listed groups. The registry entries do not establish whether all participants completed follow-up through week 19, and missing-data handling is not reported. The listed endpoint population includes randomized participants who received at least 1 dose, but other analysis populations are not described.

The adverse-event definition does not require a causal relationship, and the registry does not report detailed event-level information that would permit assessment of timing, recurrence, or treatment relatedness. The serious adverse-event term percentages are listed without enough detail to reconstruct participant-level associations. Death counts are not reported in the registry record.

Although the study objectives included pharmacokinetics, pharmacodynamics, and clinical efficacy, the relevant results are not reported in the registry record for this analysis. The record also does not report sample-size justification, interim analyses, or the rationale for the planned enrollment. Those omissions limit assessment of design adequacy and the scope of conclusions that can be drawn.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis — NCT00771030.
• Registry record last updated 2021-11-26; status last verified 2021-10.
• Results first posted 2021-11-26.
• 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

NCT00771030 is a completed randomized, quadruple-masked Phase 1 and Phase 2 study of brodalumab and placebo in adults with rheumatoid arthritis. The registry describes a sequential Phase 1b/2a design with dose escalation and dose expansion and lists enrollment of 40 participants. Brodalumab was administered by subcutaneous injection at 50 mg, 140 mg, or 210 mg, or by intravenous infusion at 420 mg or 700 mg; route-specific placebo groups were also listed.

The primary outcome counted participants with treatment-emergent adverse events from first dose through week 19. The registry reports group counts for serious and other adverse events, but lists 0 analyses. It does not report a formal comparative estimate or a detailed statistical plan. The study also included pharmacokinetic, pharmacodynamic, and clinical-efficacy objectives, but those results are not reported in the registry record for this analysis. The study started on 2008-10-27 and reached primary completion on 2010-05-25.