Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy (NCT04772313), a na phase 4 study. The primary outcome is Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6.

2. Clinical Question

3. Trial Design

This was a Phase 4, multicenter, open-label, single-group trial of pegloticase co-administered with methotrexate in participants with uncontrolled gout. Participants had previously received pegloticase monotherapy but had not maintained an sUA response; the eligibility description also includes people who stopped treatment after a clinically mild infusion reaction. Because there was no randomized comparator and no masking, the study describes outcomes during combination treatment rather than a controlled treatment contrast.

The trial was planned to include screening lasting up to 42 days, a 6-week MTX tolerability assessment, a 24-week pegloticase-plus-MTX treatment period, an optional extension of up to 24 weeks, and a 30-day post-treatment follow-up. The summary describes approximately 30 participants as the planned enrollment, while the registry record lists enrollment of 11. These are planning and enrollment figures, not an estimate of treatment effect.

The primary endpoint was assessed during Month 6, covering Weeks 20 through 24. The treatment-period description includes a Week 24, end-of-trial, or early-termination visit. Participants who stopped MTX and pegloticase before Week 24 were to remain in trial follow-up until the Week 24 visit. The optional extension was separate from the primary endpoint timeframe.

The registry lists the study as completed, with a start date of 2021-03-08 and a primary completion date of 2022-08-23. The posted record does not report a concurrent control group, a randomized allocation procedure, or masking.

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: All participants who meet the inclusion/exclusion criteria and completed the MTX Run-in Period were considered enrolled participants and received the first pegloticase infusion on Day 1. Participants who did not complete the MTX Run-in Period were considered screen failures.

MTX Run-in Period

Pegloticase + MTX Treatment Period

Reasons for not completing this period:

Pegloticase + MTX Extension Period

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) Analysis Set: all participants who receive at least 1 dose of pegloticase + methotrexate.

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: Intent to Treat (ITT) population

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6, measured over Month 6.

The primary endpoint is the percentage of participants who were sUA responders during Month 6. A responder is defined as achieving and maintaining sUA below 6 mg/dL for at least 80% of the time during Weeks 20, 21, 22, 23 and 24. The analysis population is described as the Intent-to-Treat (ITT) Analysis Set: participants who received at least one dose of pegloticase plus methotrexate.

This endpoint turns a sequence of sUA measurements over a specified period into a binary classification: each participant either meets the response definition or does not. In general, a threshold-based endpoint can make a clinical target easier to interpret than a continuous measurement alone, while also discarding information about how far above or below the threshold an individual’s measurements were. The requirement to maintain the threshold for a specified share of the Month 6 period makes the definition depend on both the level and the pattern of sUA measurements over time.

The registry record gives the endpoint definition and a 95% confidence interval as the dispersion measure, but does not report the observed responder percentage or confidence interval. It therefore does not allow the response frequency or its precision to be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main endpoint is binary at the participant level. Each participant is classified as a responder or nonresponder using the sUA threshold and the required duration below that threshold. The reported outcome is intended to be the percentage of the analysis population who qualify as responders. The registry record specifies a 95% confidence interval as the measure of dispersion, but it does not report the calculated percentage or interval.

What does the responder definition capture?

The definition combines a threshold with a time requirement. A participant must have sUA below 6 mg/dL for at least 80% of the time during Month 6, which is identified as Weeks 20, 21, 22, 23 and 24. This is not simply a measurement at one visit: the endpoint’s interpretation depends on the information used to determine sUA status across the defined period. The registry record does not describe the detailed measurement schedule or how values between measurements were handled.

In general, binary outcomes are straightforward to summarize as a proportion, but they compress information. Participants on opposite sides of a cutoff can be classified differently even when their underlying measurements are close, while variation within each classification is not conveyed by the percentage alone. The threshold and time requirement should therefore be read as the trial’s operational definition of response, not as a complete description of every participant’s sUA pattern.

How should the confidence interval be understood?

A confidence interval expresses statistical uncertainty around an estimated quantity. In general, it reflects how much the estimate might vary across repeated samples under the assumptions of the method used. Its width is influenced by the amount of information in the data and the variability of the outcome. A confidence interval does not remove design limitations, establish causality, or guarantee that the true value lies within the reported interval.

The record names a 95% confidence interval for the primary percentage but does not post the interval or the underlying responder count. The calculation method for that interval is not reported in the registry record. It would therefore be inappropriate to infer an interval method or reconstruct a primary result from the enrollment figure.

What can a single-group design estimate?

In a single-group study, the primary descriptive quantity is the outcome observed among participants who received the study regimen. Without a comparator group, the study does not estimate a randomized between-group treatment contrast. In general, before-and-after observations can be affected by time trends, changes in care, participant selection, or other influences in addition to treatment. Open-label conduct also means that participants and investigators were not masked to treatment assignment; the registry does not describe masking of outcome assessment.

The registry lists allocation as not applicable and describes a single-group model. There are no registry analyses listed. This means the posted record does not provide an inferential analysis to interpret alongside the endpoint definition. It does not establish whether analyses were conducted outside the registry record.

Why does the population definition matter?

The primary analysis population is defined as all participants who received at least one dose of pegloticase plus methotrexate. This is the registry’s stated ITT Analysis Set definition. It is important to know how the population is defined because the percentage of responders depends on which participants are included and how missing endpoint information is treated. The record does not report the number assessed for the primary endpoint, the number with missing Month 6 measurements, or how missing data were handled.

The registry distinguishes the planned enrollment of approximately 30 from the actual enrollment of 11. In general, a limited number of participants can make a proportion estimate less precise, particularly when outcomes are uncommon or vary among participants. The absent endpoint count and confidence interval prevent assessment of the actual precision in this study. No sample-size justification is reported in the registry record, and the planned enrollment figure alone does not explain the design assumptions.

How do secondary outcomes fit with the primary endpoint?

Listed secondary outcomes include the percentage of sUA responders during Month 3; specified events from Day 1 to Week 24; change in urate deposition volume measured by dual energy computed tomography to Week 24; and changes in Health Assessment Questionnaire measures at Weeks 14 and 24. The registry record provides outcome descriptions but not their results in the information available for this analysis. Their presence does not establish whether they were tested, how they were prioritized, or how results were interpreted relative to the primary endpoint. Those analysis details are not reported in the registry record.

More generally, statistical methods should be interpreted together with the design, endpoint definition, analysis population, and handling of incomplete data. For this study, the design and endpoint are described, but the primary estimate, confidence interval, analysis procedures, and missing-data approach are not reported. Those omissions limit interpretation of efficacy and precision beyond the basic endpoint specification.

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("Pegloticase Plus Methotrexate")
n      <- c(11)
events <- c(1)
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  Pegloticase Plus Methotrexate  11  1  9.1  0.2  41.3  1.6  37.7  2.1  38.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and several secondary outcomes, including Month 3 sUA response, specified events through Week 24, imaging-based urate deposition volume, and Health Assessment Questionnaire measures. The registry record does not report a multiplicity strategy, such as a prespecified ordering of tests or an adjustment to account for evaluating multiple outcomes. It is therefore not possible to determine how the study planned to control the chance of false-positive findings across outcomes, if formal hypothesis tests were conducted.

The record defines the primary ITT Analysis Set as all participants who received at least one dose of pegloticase plus methotrexate. That definition does not specify how participants without an evaluable Month 6 outcome were handled. The missing-data strategy, including any imputation, rules for early discontinuation, or sensitivity analyses, is not reported in the registry record. Although the trial description says participants who stopped treatment before Week 24 would remain in follow-up until the Week 24 visit, this does not state how unavailable endpoint measurements were incorporated into the analysis.

The registry lists no analyses. It also does not report a statistical analysis plan, an interim-analysis plan, or a sample-size justification. These details should not be inferred from the study’s endpoint, enrollment, or duration. In general, multiplicity and missing-data choices can affect how confidently results are interpreted, but those methods cannot be evaluated when they are not described. The primary estimate itself is also not reported in the registry record, so its sensitivity to these choices cannot be assessed.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: septic shock (9.1%), perineal abscess (7.7%).

The registry separates adverse-event information by period. During the MTX run-in period, 13 participants were at risk for serious events and 1 was affected; 13 were at risk for other events and 7 were affected. During the pegloticase-plus-MTX treatment period, 11 participants were at risk for serious events and 1 was affected; 11 were at risk for other events and 8 were affected. The registry reports zero deaths in each period.

The listed top serious-event terms are septic shock at 9.1% and perineal abscess at 7.7%. The registry record does not provide further context for interpreting these term percentages in the information. The event counts are descriptive and should not be interpreted as proof that treatment caused an event. The periods also have different numbers at risk, and the study has no control group for a like-for-like safety comparison.

In general, adverse-event counts describe events observed under study conditions; they do not alone establish causality or quantify comparative risk. The registry record does not report enough detail to evaluate event timing, severity beyond the serious-event categorization, or individual-level overlap between categories.

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

The registry record establishes that this was a Phase 4, open-label, single-group study of pegloticase with methotrexate in people with uncontrolled gout who had previously failed to maintain an sUA response on pegloticase monotherapy. It defines a Month 6 responder as someone with sUA below 6 mg/dL for at least 80% of the specified period. These details make clear what the trial intended to assess and in whom.

However, the record does not report the observed percentage of Month 6 responders, its 95% confidence interval, or the underlying number of responders. The posted information therefore cannot establish how often participants met the primary definition or how precisely that percentage was estimated. The listed secondary outcomes also do not have reported results in the information available for this analysis.

The design does not include a control group, so the record cannot provide a randomized comparison with pegloticase alone or another option. In general, a single-group outcome describes what happened among participants treated in the study; it does not by itself isolate the effect of treatment from other influences. The open-label design further means treatment was not masked.

The adverse-event counts and listed serious-event terms describe safety observations in the study periods, including zero deaths in each. They do not establish that treatment caused or prevented any event, and there is no control group to support comparative safety conclusions. The data should be read as descriptive observations from the enrolled participants rather than as a definitive estimate of treatment effect or comparative safety.

These distinctions matter because a protocol question, an endpoint definition, and an outcome result are different things. The registry describes the question and definition, but does not report the primary outcome estimate. No conclusion about the direction or magnitude of an efficacy result can be drawn from the registry record.

14. Why This Trial Matters Statistically

This trial addresses a population with a specific treatment history: participants had uncontrolled gout and had previously received pegloticase without a concomitant immunomodulator, then stopped after failing to maintain sUA response and/or experiencing a clinically mild infusion reaction. That context is important statistically because results from a selected group with prior treatment failure would describe that group, not automatically all people with gout or all people starting pegloticase.

The study also illustrates why endpoint definitions need to be read closely. The primary outcome is not merely an sUA value at a single visit; it requires maintaining a specified threshold for a specified share of the Month 6 period. The endpoint definition makes the intended response criterion explicit, but the registry record does not report the observed response percentage or its uncertainty.

Design features set clear limits on what can be learned. A single-group, open-label study can describe outcomes observed during combination treatment, but it cannot provide a randomized comparison with another regimen. Enrollment was 11, while approximately 30 participants were described as planned. The smaller enrolled group makes the absence of a reported estimate and confidence interval especially consequential for assessing precision; the record does not explain the enrollment difference or report a sample-size justification.

Finally, the registry’s endpoint descriptions and safety counts are not a substitute for a complete statistical analysis. The missing primary estimate, analysis details, and handling of missing data leave important questions unanswered. Recognizing these limits is part of interpreting a trial carefully: the design and intended measurement can be understood even when the posted record does not support conclusions about the size or certainty of an outcome.

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 primary limitation for interpretation is that the registry record does not report the observed Month 6 responder percentage, its 95% confidence interval, or the count of participants meeting the definition. Without those values, neither the estimated response frequency nor its precision can be assessed. The listed secondary outcomes also lack reported results in the information available for this analysis.

The study was open label and single group, with no randomized comparator. It can describe observations among participants receiving pegloticase with methotrexate, but cannot establish a controlled treatment contrast. Its participants also represent a specific group with prior pegloticase treatment and a history of not maintaining sUA response and/or a clinically mild infusion reaction; findings should not be generalized automatically to other populations.

Enrollment was 11, compared with approximately 30 planned in the study summary. The registry does not report the reason for the difference, a sample-size justification, or the statistical assumptions used to set the planned enrollment. It also does not report the endpoint analysis method, the handling of missing data, or a multiplicity strategy. The registry lists no analyses.

The safety information is limited to the reported counts by study period, deaths, and listed serious-event terms. The record does not provide a control group for comparison, and the available details do not establish causal attribution. These limitations constrain both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy — NCT04772313.
• Registry record last updated 2024-06-27; status last verified 2024-06.
• Results first posted 2023-10-10.
• 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

This completed Phase 4 trial evaluated pegloticase with methotrexate in participants with uncontrolled gout who had previously received pegloticase monotherapy but did not maintain an sUA response and/or stopped after a clinically mild infusion reaction. It was multicenter, open label, and single group, with no randomized comparator. The study summary describes approximately 30 participants as planned; the registry lists enrollment of 11.

The primary endpoint was the percentage of participants meeting the Month 6 sUA responder definition: sUA below 6 mg/dL for at least 80% of the time during Weeks 20, 21, 22, 23 and 24. The registry record does not report the observed primary result or confidence interval. It lists secondary outcomes and adverse-event information, including zero deaths in each reported period. Analysis methods, missing-data handling, and multiplicity procedures are not reported in the registry record.