Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout (NCT03994731), a randomized phase 4 study. The primary outcome is Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6.

2. Clinical Question

The question is clinically framed around maintaining a biochemical threshold over a specified assessment period, not around one isolated serum uric acid measurement. The registry record also lists safety, tolerability, pharmacokinetics, and longer-term outcomes as study interests, but the primary statistical comparison is the Month 6 responder percentage. The randomized, placebo-controlled design is intended to make the two assigned groups comparable on average, while the posted results quantify the observed difference and its uncertainty. Those results do not by themselves establish what would happen in populations or settings beyond the participants represented in the record.

3. Trial Design

This was a Phase 4, randomized, triple-masked, parallel-group study of pegloticase with methotrexate compared with pegloticase with placebo for methotrexate. The registry record reports enrollment of 152 participants and a completed status. It lists the study start as 2019-06-13 and primary completion as 2021-03-17. The sponsor was Amgen. The condition listed was gout.

The design evaluates the addition of methotrexate in participants receiving pegloticase. Both randomized groups received pegloticase; the assigned difference was blinded oral methotrexate or placebo for methotrexate. Before randomization, participants underwent a methotrexate tolerability assessment. The arm descriptions state that oral methotrexate 15 mg weekly was used during that assessment, and that participants tolerating methotrexate were randomized to blinded assigned study medication during the run-in period. The complete descriptions of treatment after the run-in are truncated in the registry record, so further dosing or administration details are not reported in the registry record.

The primary endpoint results use 100 participants in the pegloticase-plus-methotrexate group and 52 in the pegloticase-plus-placebo group. The primary analysis population is described as all randomized participants. The difference between the overall enrollment count and the arm denominators in the primary results reflects that these figures refer to different registry entries or analysis displays; a complete participant flow explaining it is not reported in the registry record.

Triple masking indicates that masking extended beyond an open-label design, but the specific masked roles are not reported in the registry record. Details of the randomization sequence, allocation concealment, stratification factors, and the trial’s original sample-size justification are also not reported in the registry record. These omissions limit assessment of implementation details, even though the registry identifies the study as randomized and reports a sponsor analysis using a stratified method.

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: This study included a 2-week MTX Tolerability Assessment Period consisting of 2 weeks oral MTX. 159 participants received MTX in this period. The 7 participants who were unable to tolerate MTX in this period or who met other exclusion criteria were not randomized, were classified as screen failures, and were not considered enrolled per protocol section 9.4.6.3.2.2. 152 randomized participants were considered enrolled in this trial.

Run-in Period (From Week -4 to Day 1)

Pegloticase + IMM Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) Population: all randomized participants.

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.

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 (Weeks 20, 21, 22, 23 and 24).

The primary endpoint is the percentage of participants who were serum uric acid responders during Month 6, defined as Weeks 20, 21, 22, 23 and 24. A responder had to achieve and maintain serum uric acid < 6 mg/dL for at least 80% of the time during that period. The definition includes specified pre-infusion, post-infusion, non-infusion, and unscheduled assessments, rather than relying on a single measurement. A participant needed at least 2 serum uric acid observations from different visits to be eligible to qualify as a responder. Participants who met the stopping rule—pre-infusion serum uric acid > 6 mg/dL at 2 consecutive scheduled visits beginning with the Week 2 visit—were counted as non-responders.

This is a binary endpoint: each participant is classified as a responder or non-responder, and the group result is the percentage classified as responders. General statistical context: a prespecified threshold can make a continuous laboratory measure easier to interpret as a response outcome, while the responder definition also discards information about how far individual measurements lie above or below the threshold. Requiring repeated assessments makes the endpoint reflect sustained control over the assessment period, but its interpretation depends on the exact measurement schedule and rules for missing or insufficient observations.

The endpoint is used to compare response proportions between the randomized groups. It does not describe every aspect of gout, symptoms, function, safety, or longer-term outcome. The registry record reports additional secondary outcomes, but the Month 6 responder percentage is the primary measure for the main comparison.

7. Results Posted in the Registry

• Pegloticase + MTX: 71.0% (71/100) versus 38.5% (20/52) on control; risk difference 32.5 percentage points (95% CI 16.6 to 48.5), risk ratio 1.85 (1.28–2.66); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Pegloticase + MTX: 60.0% (60/100) versus 30.8% (16/52) on control; risk difference 29.2 percentage points (95% CI 13.4 to 45.0), risk ratio 1.95 (1.26–3.02); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Pegloticase + MTX than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Pegloticase + MTX: 53.8% (28/52) versus 31.0% (9/29) on control; risk difference 22.8 percentage points (95% CI 1.2 to 44.4), risk ratio 1.74 (0.95–3.16); unadjusted two-proportion z-test p = 0.048.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Pegloticase + MTX than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Pegloticase + MTX: mean -0.35 versus -0.31 on control; difference -0.04 (95% CI -0.21 to 0.13), standardized effect d = -0.09; z-test p = 0.643.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pegloticase + MTX and the control. The interval gives the range of effects that remain compatible with the data.

Across the detailed secondary outcomes, the posted pattern is not uniform in how much information is available or how directly it supports comparison. The Month 12 responder endpoint and complete tophus resolution include group estimates and sponsor comparisons. The HAQ-DI outcome also includes a reported comparison, while the registry lists HAQ pain and HAQ health changes among the secondary measures without detailed results in the outcome information summarized in the record. The full set of detailed results is therefore incomplete.

These outcomes provide different perspectives from the primary Month 6 biochemical response: they include a later responder assessment, a tophus outcome, and patient-reported function, pain, or health measures. They may help contextualize the primary endpoint, but they do not redefine it. The available secondary findings should not be treated as a single confirmatory body of evidence because the outcomes differ in measurement, assessment time, available sample size, and statistical method.

The registry record does not report a multiplicity strategy. General statistical context: examining multiple outcomes increases the chance that at least one result will appear statistically notable by chance, especially when each is assessed without adjustment. An unadjusted secondary p-value should consequently carry less weight than a prespecified primary analysis and should generally be interpreted as exploratory unless the analysis plan establishes otherwise. The registry record does not report enough planning detail to determine the intended inferential status of each secondary outcome. The secondary results can inform the overall picture, but they do not independently establish a broad treatment effect across all measured domains.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12
• Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52
• Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
• Mean Change From Baseline HAQ Pain Score at Week 52
• Mean Change From Baseline in HAQ Health Score at Week 52

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either met the responder definition or did not. The arm percentages describe the proportion of participants classified as responders. The primary endpoint’s repeated-measure definition includes serum uric acid assessments during Month 6, with a minimum observation requirement and a rule that classifies participants meeting the stopping criterion as non-responders. These rules determine who can count as a responder and how the endpoint represents sustained threshold attainment.

What does the sponsor’s method estimate?

The registry reports a Cochran-Mantel-Haenszel analysis with a stratified difference in proportions. General statistical context: the Cochran-Mantel-Haenszel approach combines information across strata to estimate or test an association while accounting for a stratification structure. The registry record does not report the specific strata or their role in randomization, so the details of that adjustment cannot be assessed from the posted information. The reported estimate is 32.31, its 95% confidence interval is 16.3 to 48.3, and the reported p-value is < 0.001. The analysis is labelled a superiority analysis.

A stratified estimate can differ from a direct, unadjusted comparison of the overall group proportions. That does not necessarily imply an error: the two methods may use different information and target slightly different summaries. The unadjusted recalculation uses the posted arm-level responder proportions and sample sizes. It gives a risk difference of 0.325, a 95% confidence interval from 0.166 to 0.485, and p < 0.001. These recalculations are not a substitute for the sponsor’s analysis, which is the registry’s reported analysis.

How should the p-value be understood?

General statistical context: a p-value is calculated under a null hypothesis and a model for the data. It measures how incompatible the observed data, or data more extreme, are with that null model. It is not the probability that the treatment has no effect, and it does not state the probability that the observed estimate will be replicated. The p-value should be read alongside the estimated group difference, confidence interval, study design, and analysis assumptions. A small p-value can coexist with uncertainty about the exact size of the difference.

The primary endpoint is a percentage, while a risk difference compares the underlying proportions on an absolute scale. The recalculated risk difference is reported on the proportion scale, and the sponsor’s estimate is reported in the registry as 32.31. The record does not state the unit formatting convention for that sponsor estimate beyond “stratified difference in proportions”; it is therefore important to retain the sponsor’s reported number and interval rather than silently converting scales.

Why can over-dispersion matter?

General statistical context: for binary outcomes, a simple model may assume that the variability is fully described by the binomial distribution and the underlying response probability. If outcomes are more variable than that model allows, the data are over-dispersed. Ignoring over-dispersion can make standard errors too small and confidence intervals too narrow. The registry record does not report an over-dispersion assessment or indicate that over-dispersion was a concern for this analysis, so no conclusion about it can be drawn from the reported results.

For continuous secondary outcomes, methods and assumptions differ from those for a binary response. The HAQ-DI result is reported as a least-squares mean change and its comparison uses an MMRM ANCOVA method. General statistical context: a mixed model for repeated measures can use multiple measurements over time and model their correlation; ANCOVA can account for baseline values or other specified covariates. The exact model terms, covariance structure, and missing-data assumptions are not reported in the registry record. The reported difference is -0.04, with a 95% confidence interval from -0.21 to 0.13 and p = 0.629.

Other listed secondary outcomes include a Month 12 responder percentage, complete resolution of at least one tophus at Week 52, and changes in HAQ pain and health scores at Week 52. The registry record lists six analyses and five secondary outcomes, but not all detailed secondary results appear in the available outcome details. The methods used for each unreported secondary analysis are not reported in the registry record. Each endpoint also has its own measurement scale and analysis population, so results should not be treated as interchangeable.

Finally, the original trial protocol and statistical plan details are not reported in the registry record. In particular, the original sample-size justification, planned interim analyses, full missing-data strategy, and multiplicity adjustment are not reported in the registry record. General statistical context: these details help establish which analyses were planned in advance and how to interpret multiple outcomes and incomplete follow-up. Their absence limits independent evaluation of those aspects, but it does not change the numerical results that are posted.

11. Confidence Intervals and Precision

Confidence intervals express uncertainty around an estimated quantity under the assumptions of the analysis. General statistical context: a 95% confidence interval is produced by a procedure that, under repeated use in comparable conditions and if its assumptions hold, would cover the target quantity in 95% of such intervals. It is not a guarantee that the particular interval contains the true value, and it does not mean that 95% of participants had outcomes inside the interval.

For the Month 6 endpoint, the sponsor reports a stratified difference of 32.31 with a 95% confidence interval from 16.3 to 48.3. This interval gives a range of values compatible with the data and analysis, rather than a single exact effect. The arm-specific response intervals are 61.1 to 79.6 for pegloticase with methotrexate and 25.3 to 53.0 for pegloticase with placebo. These intervals describe uncertainty in each group’s response percentage; they should not be used as a substitute for the confidence interval on the between-group difference.

The unadjusted recalculation gives a risk difference of 0.325 and a 95% confidence interval from 0.166 to 0.485. Its interval is based on the posted arm summaries and is not the same as the sponsor’s stratified interval. The sponsor’s estimate and interval take precedence as the trial’s reported analysis. The interval’s width indicates that the exact magnitude is not determined precisely, even though the reported range is on the positive side of no difference.

Precision is influenced by the number of participants contributing information, the outcome variability, the analysis method, and the amount and handling of missing data. General statistical context: wider intervals indicate greater uncertainty about the size of an effect, while narrower intervals indicate greater precision under the model. The trial’s reported arm sizes for the primary results are 100 and 52. The registry record does not report enough detail about missing observations or the stratification structure to independently reconstruct the sponsor interval or explain all of its width.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations express sample size as participants per arm, not as the total across both groups and not as total events. They are based on a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect to detect is the stated fraction of the observed effect. The figures are illustrations calculated from the observed effect, not the original design justification for the trial; that original justification is not reported in the registry record.

The 80% power column gives the approximate participants per arm required for an analysis to have an 80% chance of rejecting the no-difference null hypothesis if the assumed effect and planning assumptions were true. The 90% power column gives the corresponding planning count for a 90% chance. These are conditional planning probabilities, not guarantees about the result of a future study. For the primary endpoint, the illustrations range from 36 participants per arm for 100% of the observed effect at 80% power to 147 participants per arm for 50% of the observed effect at 80% power. The corresponding 90% power illustrations range from 48 to 196 participants per arm across those same effect assumptions.

Smaller effects are harder to distinguish from random variation, so they require more participants under otherwise fixed assumptions. The illustrations therefore increase as the assumed fraction of the observed effect decreases. They are not observed power: observed power is not a useful way to reinterpret the result after the trial, and these values do not report the probability that the trial’s finding is true. They also should not be read as evidence that the original trial was designed around the observed effect, because its own design assumptions are not reported in the registry record.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.385; treatment proportion p₁ = 0.710; average p̄ = 0.547.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7039 = 1.3797.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6653 = 0.5599.
4. n = (1.3797 + 0.5599)² / (0.3254)² = 35.5, rounded up to 36 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.384615384615385                          # control proportion
p1 <- 0.71                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3994731)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 36 (80% power), 48 (90% power)
 75% of observed effect: n per arm = 65 (80% power), 87 (90% power)
 50% of observed effect: n per arm = 147 (80% power), 196 (90% power)
power.prop.test: 35.5 
Simulated power at n = 36 per arm: 0.796 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor’s primary analysis is the registry-reported Cochran-Mantel-Haenszel analysis. It estimates a stratified difference in proportions of 32.31, with a 95% confidence interval from 16.3 to 48.3 and p < 0.001. This is the main reported inferential result and should take precedence over the simple recalculation from the posted arm summaries.

The recalculated unadjusted comparison uses the displayed responder proportions and sample sizes. It estimates a risk difference of 0.325, with a 95% confidence interval from 0.166 to 0.485 and p < 0.001. It is an unadjusted comparison, unlike the sponsor’s stratified analysis. Small differences between estimates, intervals, or p-values can arise when analyses use different methods or account for stratification differently. The registry record does not give the strata or detailed model specification needed to reproduce the sponsor result independently.

There is no reported discrepancy flag. The recalculation is therefore best read as a transparent check based on the displayed group summaries, not as a replacement or correction of the sponsor analysis. Both analyses point to a higher observed Month 6 response proportion in the pegloticase-plus-methotrexate group, while the sponsor’s method remains the designated reported result.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and multiple secondary outcomes, but a multiplicity adjustment or testing hierarchy is not reported in the registry record. General statistical context: when several hypotheses are tested, the chance of at least one false-positive result can rise if each is judged at the same nominal threshold without accounting for the family of tests. Strategies such as a prespecified hierarchy or adjustment can control that risk, but it is not possible to say which strategy was used without the relevant plan. The primary outcome should therefore be distinguished from secondary findings, particularly when secondary p-values are unadjusted.

The endpoint description specifies an intent-to-treat population consisting of all randomized participants. It also specifies that participants with insufficient serum uric acid observations cannot qualify as responders and that participants meeting the stated stopping rule count as non-responders. These are important endpoint rules, but the broader missing-data procedures are not reported in the registry record. The record does not explain how missing measurements outside these stated rules were handled, whether imputation was used, or what sensitivity analyses assessed the effect of missingness.

The registry provides arm-specific primary endpoint denominators of 100 and 52, while overall enrollment is 152. A participant flow accounting for these counts and describing exclusions, withdrawals, and missing outcome data is not reported in the registry record. The available record also does not give the full analysis population definitions for every secondary endpoint. Consequently, the reader cannot determine from these details alone whether all randomized participants contributed to every secondary analysis or how missing data may have affected those estimates.

The original statistical analysis plan, including any interim analyses and sample-size justification, is not reported in the registry record. General statistical context: knowing whether analyses were prespecified helps distinguish confirmatory testing from analyses selected after outcomes were observed. The absence of these details does not establish that a particular procedure was or was not used; it means that independent assessment of those choices is limited.

16. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaphylactic reaction (4.1%), covid-19 (2.1%), inappropriate antidiuretic hormone secretion (2.0%), non-cardiac chest pain (2.0%), abscess soft tissue (2.0%).

Safety counts are reported for distinct study periods and participant groups, so they should be read with their period-specific denominators. During the methotrexate tolerability assessment, 159 participants were at risk; 0 were reported with a serious adverse event and 45 with another adverse event. During the pegloticase-plus-methotrexate run-in period, 98 were at risk, 1 had a serious adverse event, and 28 had another adverse event. During the pegloticase-plus-placebo run-in period, 51 were at risk, 0 had a serious adverse event, and 10 had another adverse event.

During the pegloticase-plus-immunomodulation period, 96 participants in the methotrexate group were at risk; 13 had a serious adverse event, 71 had another adverse event, and 2 deaths were reported. In the corresponding placebo group, 49 were at risk; 5 had a serious adverse event, 42 had another adverse event, and no deaths were reported. These are counts of affected participants as displayed, not counts of all episodes. The registry does not state in these figures whether events were considered treatment-related, nor does it provide enough detail to attribute deaths to a cause or treatment.

The serious terms listed include anaphylactic reaction at 4.1%, Covid-19 at 2.1%, inappropriate antidiuretic hormone secretion at 2.0%, non-cardiac chest pain at 2.0%, soft tissue abscess at 2.0%, and facial bones fracture at 2.0%. Safety counts are descriptive and should be interpreted with the differing periods and denominators in mind; they do not by themselves establish comparative risk.

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

The posted primary result shows a greater Month 6 serum uric acid responder percentage in the pegloticase-plus-methotrexate group than in the pegloticase-plus-placebo group. The sponsor’s stratified analysis reports a positive difference with a confidence interval that does not include zero, and a p-value of < 0.001. The group percentages and their uncertainty describe an average comparison in the randomized study population, not a prediction for any particular participant.

The result concerns a specific endpoint: meeting the serum uric acid threshold over the Month 6 assessment period under the registry’s response and stopping rules. It does not by itself establish effects on every symptom, functional outcome, longer-term health outcome, or safety outcome. The secondary endpoints are relevant context, but not all detailed secondary results are available, and the multiplicity strategy is not reported in the registry record.

The trial compares pegloticase with methotrexate against pegloticase with placebo for methotrexate. It therefore addresses the addition of methotrexate within this treatment comparison; it is not a comparison of pegloticase against no pegloticase. The population is also shaped by the methotrexate tolerability assessment and randomization of participants who tolerated methotrexate, as described in the registry record. This should be kept in mind when considering how well the findings apply outside the randomized study population.

Confidence intervals express uncertainty about the magnitude of the group difference, and the reported interval still allows a range of possible values. The results do not prove a particular biological mechanism, establish that every participant had a response, or determine the balance of benefits and harms for an individual. The registry record’s incomplete details on missing-data procedures, analysis specifications, and multiplicity further limit what can be concluded from the posted summaries alone. The numerical findings are best interpreted as evidence about this trial’s defined comparison and outcomes, with the reported uncertainty and record limitations kept in view.

18. Why This Trial Matters Statistically

This trial illustrates how a responder endpoint can turn repeated laboratory measurements into a clinically interpretable group comparison. The Month 6 definition requires sustained serum uric acid below a threshold for a specified proportion of the assessment period, includes a minimum observation requirement, and treats participants meeting a stopping rule as non-responders. Those rules make the estimand more specific than a simple comparison of one laboratory value at one visit.

It also demonstrates why the analysis method matters. The sponsor reports a stratified difference using the Cochran-Mantel-Haenszel method, while a recalculation from the displayed arm summaries gives an unadjusted risk difference. Each summarizes the randomized comparison differently. The sponsor analysis is the reported result, and its confidence interval and p-value should not be conflated with the unadjusted calculation.

The record also shows why estimates need to be read with precision and design context. A positive difference and a small p-value do not specify the exact effect for future populations, nor remove uncertainty about its magnitude. The primary comparison has different arm sizes, and details of the stratification, missing-data procedures, and multiplicity plan are not reported in the registry record.

Finally, a completed randomized study can contribute evidence while still leaving important statistical questions unanswered in the registry record. Distinguishing the primary endpoint from secondary outcomes, interpreting period-specific safety counts, and separating sponsor analyses from summary-based recalculations are central to responsible reading of clinical trial results. These practices help keep a numerical finding tied to the question it actually addresses.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several limitations are specific to interpreting this trial from the registry record. The arm descriptions are truncated after the run-in period, so the complete treatment schedules and further administration details are not reported in the registry record. Triple masking is reported, but which groups of people were masked is not reported in the registry record. Randomization sequence generation and allocation concealment details are also not reported in the registry record.

The record gives enrollment of 152 and primary endpoint arm counts of 100 and 52, but does not provide a participant flow that explains the counts across screening, randomization, follow-up, and analysis. It describes the primary population as intent-to-treat, yet the handling of missing serum uric acid data beyond the stated responder eligibility and stopping rules is not reported in the registry record. This limits assessment of potential bias from missing observations or attrition.

The sponsor’s primary analysis is stratified, but the strata and detailed model specification are not reported in the registry record. The unadjusted recalculation uses summary statistics and cannot reproduce or replace that analysis. The original sample-size justification, interim analyses, full statistical analysis plan, and multiplicity approach are not reported in the registry record. These omissions make it harder to assess which analyses were prespecified and how the planned error rate was handled across endpoints.

Detailed results are not available for every listed secondary outcome in the record information. Safety data are organized by periods with different denominators; the posted counts do not establish event relatedness or explain the causes of deaths. These limitations call for restrained interpretation of the available summaries, rather than assumptions about unreported methods or outcomes.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout — NCT03994731.
• Registry record last updated 2024-06-26; status last verified 2024-06.
• Results first posted 2022-05-16.
• 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.

23. Record Summary

The registry describes a completed Phase 4 randomized, triple-masked, parallel-group study of pegloticase with methotrexate versus pegloticase with placebo for methotrexate in adults with uncontrolled gout. Enrollment was 152, and the primary endpoint was the percentage of intent-to-treat participants meeting the sustained serum uric acid response definition during Month 6.

The response percentages were 71.0% with methotrexate and 38.5% with placebo for methotrexate. The sponsor’s Cochran-Mantel-Haenszel analysis reported a stratified difference of 32.31, with a 95% confidence interval from 16.3 to 48.3 and p < 0.001. The summary-based unadjusted recalculation is distinct from that sponsor analysis.

Secondary outcomes and period-specific safety counts provide additional context, but complete details on multiplicity, missing-data handling, and several analysis specifications are not reported in the registry record. Findings should therefore be interpreted in relation to the defined primary endpoint and the limits of the posted record.