Combining Lesinurad With Allopurinol in Inadequate Responders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combining Lesinurad With Allopurinol in Inadequate Responders (NCT01493531), a randomized phase 3 study. The primary outcome is Subjects With a Serum Urate (sUA) < 6.0 mg/dL by Month 6..

2. Clinical Question

The trial’s stated purpose was to compare serum uric acid lowering, clinical benefits, and safety for lesinurad combined with allopurinol versus allopurinol alone in people whose response to allopurinol was inadequate. The primary endpoint operationalizes the urate-lowering part of that question as a threshold outcome: whether a participant reached a serum urate level below 6.0 mg/dL by Month 6. The endpoint is therefore about the proportion meeting that threshold, not the average change in serum urate or the amount of change for each participant.

The registry lists three groups: lesinurad 200 mg plus allopurinol, lesinurad 400 mg plus allopurinol, and placebo plus allopurinol. The posted primary proportions are 0.554, 0.665, and 0.233, respectively. The registry also reports Cochran-Mantel-Haenszel comparisons against placebo plus allopurinol. Those reported analyses are central to interpretation because the simple re-calculation from posted summary statistics does not agree with the registry’s own results.

This is a question about the measured outcome in this particular trial and how precisely the posted analyses estimate the between-group differences. It does not by itself establish the broader clinical importance of reaching the threshold, or answer questions about longer-term outcomes beyond those listed in the registry record.

3. Trial Design

This was a Phase 3, randomized, triple-masked, parallel-group study. The registry describes a multicenter, placebo-controlled combination study. Its official title identifies the comparison as lesinurad and allopurinol versus allopurinol alone in subjects with gout who had an inadequate hypouricemic response to standard-of-care allopurinol. The registry lists an enrollment of 610 and marks the study as completed.

Participants were assigned to one of three listed groups: lesinurad 200 mg plus allopurinol, lesinurad 400 mg plus allopurinol, or placebo plus allopurinol. The posted arm sizes for the primary endpoint are 204, 200, and 206, respectively. The registry describes the primary analysis population as the Intent-to-Treat Population. The endpoint was assessed by Month 6, while the listed secondary outcomes include gout flares over 12 months and resolution of at least one target tophus by Month 12 among participants with at least one target tophus at baseline.

The registry gives a study start of 2011-12 and a primary completion of 2014-05. It does not report the randomization procedure, the specific roles included in triple masking, or details of the treatment schedule beyond the named groups. It also does not report the protocol’s sample-size justification or the planned handling of missing endpoint values. Those details should not be inferred from the study’s phase, masking, or enrollment.

The parallel-group structure means that the listed arms represent separate assigned groups rather than repeated treatment periods for each participant. The placebo-plus-allopurinol group provides the comparator for each lesinurad combination. The registry’s reported primary analyses use a Cochran-Mantel-Haenszel method, but the registry record does not identify the stratification factors or any adjustment variables. These omissions limit what can be concluded about the exact analysis implementation.

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: Intent-to-Treat Population

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 Subjects With a Serum Urate (sUA) < 6.0 mg/dL by Month 6., measured over 6 months.

The primary endpoint is the proportion of participants in the Intent-to-Treat Population whose serum urate (sUA) level was below 6.0 mg/dL by Month 6. It is a binary threshold endpoint: each participant either met the specified threshold by the specified time or did not. The registry reports the endpoint as a proportion of subjects, rather than as a mean serum urate level or an average change from baseline.

A threshold outcome can be useful when a study’s question is framed around reaching a prespecified level. It converts each participant’s measurement into a common yes-or-no status, which can then be summarized as the share of the group meeting the criterion. As a general statistical point, this makes the endpoint straightforward to describe, but it also discards information about how far each participant’s measurement was above or below the threshold. Two participants with different serum urate values may count the same way if both fall on the same side of the cutoff.

The registry reports proportions of 0.554 for lesinurad 200 mg plus allopurinol, 0.665 for lesinurad 400 mg plus allopurinol, and 0.233 for placebo plus allopurinol. The reported comparisons estimate risk differences and include 95% confidence intervals and p-values. Because the simple re-calculation from the posted summary statistics conflicts with the registry’s reported analyses, the sponsor’s own reported analyses take precedence when describing the primary comparison.

The endpoint addresses status by Month 6. It does not, on its own, describe the timing of reaching the threshold, persistence after Month 6, or a participant’s clinical experience. The registry does not report further detail about how missing Month 6 measurements were handled.

7. Results Posted in the Registry

• Lesinurad 200 mg + Allopurinol: 0.5% (1/204) versus 0.0% (0/206) on control; risk difference 0.5 percentage points (95% CI -0.5 to 1.4); unadjusted two-proportion z-test p = 0.314.
• Lesinurad 400 mg + Allopurinol: 0.5% (1/200) versus 0.0% (0/206) on control; risk difference 0.5 percentage points (95% CI -0.5 to 1.5); unadjusted two-proportion z-test p = 0.310.

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.

Gout Flares

• 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 deviations.
• Result:
  • Lesinurad 200 mg + Allopurinol: mean 0.70 versus 0.90 on control; difference -0.20 (95% CI -0.51 to 0.11), standardized effect d = -0.12; z-test p = 0.209.
  • Lesinurad 400 mg + Allopurinol: mean 0.80 versus 0.90 on control; difference -0.10 (95% CI -0.44 to 0.24), standardized effect d = -0.06; z-test p = 0.565.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lesinurad 200 mg + Allopurinol and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lesinurad 400 mg + Allopurinol and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists two secondary outcomes with posted results: gout flares over 12 months and resolution of at least one target tophus by Month 12 among participants who had at least one target tophus at baseline. It also lists gout flares as a count-style outcome summarized by means and standard deviations, with negative binomial regression used for the reported comparisons. The posted sponsor analyses for flares do not show the same clear statistical pattern as the primary endpoint: their reported p-values are 0.572 and 0.745, and their confidence intervals include the null value for a ratio.

This broad contrast means that the registry’s reported primary finding should not be generalized automatically to the other measured outcomes. Different endpoints capture different aspects of the study, use different scales, and may have different precision. A threshold outcome at Month 6 is not interchangeable with a count of flares over 12 months or with a tophus-resolution outcome. The registry record does not report results for the listed tophus-resolution outcome, so no conclusion about its observed pattern can be drawn from the record.

Secondary analyses generally carry less weight when they are not designated as the primary question, especially when many outcomes or comparisons may be examined. In general, repeated testing can increase the chance of seeing apparently notable results by chance if no multiplicity strategy is used. The registry record does not report whether multiplicity was addressed, whether the secondary outcomes had prespecified testing order, or whether their analyses were intended to support confirmatory conclusions. The secondary results are therefore best read as additional, outcome-specific evidence, not as a substitute for the primary analysis or as a comprehensive account of clinical benefit.

The secondary findings also do not resolve the primary-analysis discrepancy. They come from a distinct endpoint and model, and their interpretation depends on their own assumptions and missing-data handling, details that are not fully reported. The overall record therefore supports a careful separation of the primary result from the secondary outcome evidence, with no assumption that a result for one measure establishes the result for another.

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

• Gout Flares
• Subjects With ≥ 1 Target Tophus at Baseline Who Experience Complete Resolution of at Least 1 Target Tophus by Month 12

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary: it records whether a participant had serum urate below 6.0 mg/dL by Month 6. The registry reports the percentage-style proportions in each group and gives risk-difference comparisons against placebo plus allopurinol. A risk difference expresses the difference between two group proportions on the same probability scale. In general, it is an absolute contrast, not a relative ratio. The registry reports the sponsor’s risk-difference estimates as 0.32 and 0.43, with 95% confidence intervals of 0.23 to 0.41 and 0.34 to 0.52, respectively.

The reported primary method is the Cochran-Mantel-Haenszel method. In general, this method can combine information across strata when comparing groups, rather than treating all observations as though they came from one undivided stratum. The registry record does not identify the strata or describe the exact implementation, so no particular adjustment factor or stratification scheme can be attributed to this analysis. The method name alone does not show which participant characteristics, if any, were used.

The record also permits a simple, unadjusted re-calculation using posted arm summaries. That re-calculation does not agree with the sponsor’s reported comparisons: its estimates are near zero, and its confidence intervals include zero, unlike the sponsor’s reported estimates and intervals. Because this discrepancy is true, the sponsor’s own analysis takes precedence. The registry record does not explain why the two approaches yield such different values. Readers should distinguish the posted proportions, the sponsor-reported inferential results, and the simple re-calculation rather than treating them as interchangeable.

What does a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimate. A narrower interval indicates greater precision under the analysis assumptions, while a wider interval indicates less precision. It does not describe the range of individual participant outcomes, and it is not a probability statement about a fixed parameter after the interval has been calculated. Here, the registry reports 95% intervals for the primary risk differences. Their position relative to zero is relevant to the direction and statistical compatibility of the comparison, but the interval does not determine whether a difference is clinically important.

How should p-values be read?

In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under the chosen statistical model. It is not the probability that the null hypothesis is true, and it does not quantify the size or importance of an effect. The registry reports p-values of < 0.001 for both primary comparisons. These belong to the sponsor-reported analyses. The recalculated p-values are different, another aspect of the discrepancy, and should not replace the reported analyses.

Why can over-dispersion matter for count outcomes?

As a general statistical point, count outcomes such as recurrent flares can show more variability than a simple Poisson model expects. Negative binomial regression is one approach that can accommodate this extra variability, often called over-dispersion. The registry reports negative binomial regression for the gout-flare analyses. The registry does not provide enough detail to assess model specification, covariates, or whether the model’s assumptions were checked. The mean and standard deviation summaries and the negative-binomial estimates are different summaries of the endpoint and should not be assumed to be numerically equivalent.

For the flare outcome, the registry reports risk ratios with 95% confidence intervals and p-values from negative binomial regression. A risk ratio compares rates or expected counts on a relative scale, whereas the simple re-calculation uses a difference between group means. Those measures answer different statistical questions. General guidance is that a confidence interval for a ratio is interpreted relative to one, while a confidence interval for a difference is interpreted relative to zero.

What do the sample-size illustrations represent?

The planning illustrations use the observed effect as a reference and display hypothetical group sizes for detecting specified fractions of that effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For the flare comparisons, the listed values are participants per arm for 80% and 90% power under those assumptions. They are planning illustrations, not the trial’s documented design calculation and not observed power. The registry record does not report the trial’s own sample-size justification, so the illustrations cannot be used to reconstruct it.

In general, planning calculations depend on assumptions about the effect to detect, variability, significance level, allocation, and analysis. If an effect is smaller than the one used as a reference, a larger sample is generally needed to achieve the same target power, all else held constant. This is a general relationship, not a new calculation about the trial. The displayed planning values should be read as conditional examples, not as evidence that the completed trial had a particular power.

11. Confidence Intervals and Precision

The registry reports 95% confidence intervals for both primary risk-difference comparisons. For lesinurad 200 mg plus allopurinol versus placebo plus allopurinol, the reported estimate is 0.32, with a 95% interval from 0.23 to 0.41. For lesinurad 400 mg plus allopurinol versus placebo plus allopurinol, the estimate is 0.43, with a 95% interval from 0.34 to 0.52. Both reported intervals lie above zero. These intervals convey the precision of the sponsor’s estimates under the reported analysis; they do not address the reason for the discrepancy with the simple re-calculation.

The simple re-calculated comparisons have confidence intervals that include zero, in contrast to the sponsor’s intervals. That disagreement makes it important not to present the two sets of estimates as if they were alternative rounded versions of the same result. The source of the discrepancy is not reported in the registry record. The sponsor’s own analysis takes precedence, while the conflicting re-calculation is a reason for caution about interpreting the posted summaries as sufficient to reproduce the reported analysis.

In general, an interval’s width reflects statistical uncertainty under the model and data used; it does not capture all uncertainty about study conduct, measurement, analysis choices, or applicability to other populations. Confidence intervals are also not ranges containing most individual participants’ outcomes. They describe uncertainty about a group-level estimate.

The posted arm proportions provide descriptive context, but precision for those proportions is distinct from precision for a between-group difference. The record does not provide confidence intervals around the proportions themselves. Nor does it report detailed missing-data methods or sensitivity analyses that might help assess how robust the endpoint comparisons are to unobserved outcomes. Thus the confidence intervals quantify uncertainty for the sponsor-reported risk differences, but they do not resolve every limitation of the available record.

12. Analyses Reported by the Sponsor

The sponsor-reported primary analyses compare each lesinurad combination with placebo plus allopurinol using the Cochran-Mantel-Haenszel method. They report risk differences of 0.32 and 0.43, with 95% confidence intervals of 0.23 to 0.41 and 0.34 to 0.52, and p-values of < 0.001 for both comparisons. These are the registry’s own inferential results and take precedence over simple recalculations.

The reason for that precedence is a material mismatch: re-calculations from the posted summary statistics produce estimates near zero and intervals that include zero, rather than the positive differences and intervals reported by the sponsor. The reported arm proportions themselves are 0.554, 0.665, and 0.233. The registry record does not explain how the reported analysis relates to those proportions or what accounts for the conflicting re-calculation. No explanation should be assumed.

The sponsor’s analysis should therefore be described as the reported trial result, while the re-calculation should be treated as a diagnostic inconsistency rather than a replacement result. This distinction does not remove the uncertainty associated with the reported confidence intervals or settle questions about analysis details that are not reported. It makes the provenance of each estimate essential: readers should know whether a value comes from the registry’s reported model or from a simple unadjusted calculation using posted summaries.

13. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity plan for the primary and secondary outcomes, the two lesinurad dose comparisons, or any other analyses. In general, multiplicity concerns arise when several hypotheses are tested: without an appropriate strategy, the chance of at least one false-positive result can increase. This general concern does not establish that the analyses were or were not adjusted. The record simply does not report how multiplicity was handled.

The primary endpoint names the Intent-to-Treat Population. The record does not provide a detailed definition of that population or explain how participants with missing Month 6 measurements were handled. It does not report whether missing values were imputed, treated as failures, excluded from the denominator, or addressed through sensitivity analyses. These methods can affect a binary endpoint, so the absence of detail limits independent assessment of the reported results.

The registry record also does not report the protocol’s sample-size justification, interim analyses, or a full statistical analysis plan. The planning illustrations associated with the flare re-calculations are based on stated hypothetical assumptions and the observed effect; they are not evidence of the trial’s original design rationale or observed power. No claim about an interim look, stopping boundary, or prespecified multiplicity adjustment can be made from the information reported.

These omissions do not mean that the trial lacked such procedures. They mean that they are not reported in the registry record. This distinction matters: readers can describe the posted analysis and its stated population, but cannot fill gaps by assuming common practices or by inferring procedures from the trial’s phase, enrollment, or masking. The reported primary results should be considered alongside these limits in the transparency of the available analysis details.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0.02% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (1.5%), gout (1.0%), osteoarthritis (1.0%), nephrolithiasis (1.0%), pneumonia (1.0%).

The registry reports serious adverse events in 9 of 204 participants in the lesinurad 200 mg plus allopurinol group, 19 of 200 in the lesinurad 400 mg plus allopurinol group, and 8 of 206 in the placebo-plus-allopurinol group. It also reports other adverse events in 85, 82, and 60 participants in those respective groups. These are counts of participants affected as recorded in the registry. They do not by themselves describe event severity beyond the serious-event classification, duration, recurrence, or causal attribution.

The registry lists serious-event terms and percentages, including myocardial infarction at 1.5%, gout at 1.0%, osteoarthritis at 1.0%, nephrolithiasis at 1.0%, pneumonia at 1.0%, and coronary artery disease at 0.5%. The listing does not identify arm-specific percentages for these terms in the information reported. The registry does not report death counts; deaths are therefore not reported in the registry record.

In general, adverse-event counts are descriptive safety information. They should not be treated as proof that an event was caused by a treatment, nor do counts alone establish comparative risk. Interpretation depends on definitions, exposure, follow-up, event ascertainment, and analysis details. The available record does not provide enough information to draw a broader safety conclusion from these figures alone.

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

The registry’s primary analyses report positive risk differences for both lesinurad combinations compared with placebo plus allopurinol on the endpoint of reaching serum urate below 6.0 mg/dL by Month 6. The reported 95% confidence intervals are above zero, and the reported p-values are < 0.001. These results describe the registry’s reported analysis of that endpoint in the stated population.

They do not establish that every participant experienced the same outcome, because the endpoint is a group proportion. They do not describe the amount of serum urate change for participants who did or did not meet the threshold. Nor do they establish an effect on every listed clinical outcome, since gout flares and tophus resolution are distinct measures and the registry does not report results for the listed tophus-resolution outcome.

The results also should not be read as resolving the mismatch between the reported primary analyses and the simple re-calculation from posted summary statistics. The sponsor’s own analysis takes precedence, but the discrepancy remains unexplained in the registry record. It is a limitation in the reproducibility of the posted comparison, not a basis for silently substituting one estimate for another.

Statistical significance and clinical importance are different questions. In general, a small p-value indicates incompatibility with a specified null model, not the importance of an effect to participants. The registry record does not define a threshold for clinical importance for the primary risk difference. It also does not report all details needed to evaluate missing data, multiplicity, or the trial’s original sample-size rationale.

Finally, the findings pertain to the studied groups, endpoint, and follow-up described in the record. The record alone does not establish how results apply to people outside the trial population, to other treatment settings, or to outcomes beyond those reported. These statistical descriptions are not medical advice and do not determine an individual treatment choice.

16. Why This Trial Matters Statistically

This trial illustrates why reading a reported treatment comparison involves more than looking at arm-level proportions. The posted primary proportions are descriptive summaries, while the registry’s inferential results come from a named analysis method and are expressed as risk differences with confidence intervals and p-values. In this case, a simple re-calculation from the summary statistics conflicts substantially with the sponsor-reported estimates. Recognizing that mismatch is important for transparent interpretation and reproducibility.

It also shows why endpoint definitions matter. The primary outcome is a threshold status at Month 6, while a flare count over 12 months and a tophus-resolution outcome represent different questions. Statistical evidence for one endpoint should not be extended automatically to another. The distinction between an absolute risk difference and a relative ratio also matters: estimates on different scales are not direct substitutes, and their null values differ.

Another statistical lesson is that precision and importance are separate. Confidence intervals communicate uncertainty around estimates, while p-values address compatibility with a null hypothesis under a model. Neither alone establishes clinical relevance. Similarly, planning sample sizes from observed effects can illustrate how assumptions affect required enrollment, but such illustrations are not observed power and do not reveal the trial’s original design justification.

Finally, the record highlights the value of reporting analysis populations, missing-data methods, multiplicity procedures, stratification details, and the rationale for sample size. When those elements are absent, readers can describe the posted findings but cannot fully reconstruct the analysis or assess its robustness. Keeping those boundaries explicit is central to sound statistical interpretation.

17. 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.

The primary-analysis discrepancy is a trial-specific limitation in interpreting the registry record. The sponsor-reported risk differences and the simple re-calculations from posted summary statistics do not agree, and the registry record does not explain why. The sponsor’s own analysis takes precedence, but the discrepancy limits independent reproduction from the posted summaries.

The primary endpoint is a binary threshold at Month 6. As a general limitation of threshold outcomes, a participant’s measurement is reduced to whether it falls on one side of the cutoff, so information about the size of measurements and changes is not represented in the endpoint summary. The registry does not report confidence intervals for the arm proportions themselves.

The reported method is identified as Cochran-Mantel-Haenszel, but the stratification variables and implementation details are not reported in the registry record. The record also does not report the full statistical analysis plan, missing-data handling, sensitivity analyses, multiplicity procedures, interim analyses, or the trial’s sample-size justification. These omissions limit evaluation of how robust the results are to analysis choices and how the analyses relate to the original protocol.

Only two secondary outcomes have posted results, while the registry lists a tophus-resolution outcome without results. The record therefore does not provide a complete outcome-level account of all listed secondary measures. The adverse-event summaries are also limited: the posted event counts do not give causal attribution or detailed event timing, and the listed serious-event percentages are not presented by treatment group in the information reported. Death counts are not reported in the registry record.

These are limits of what the registry record reports, not proof that unreported procedures or information did not exist. They constrain the conclusions that can be drawn from the posted record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Combining Lesinurad With Allopurinol in Inadequate Responders — NCT01493531.
• Registry record last updated 2016-05-26; status last verified 2016-04.
• Results first posted 2016-05-26.
• 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.

21. Record Summary

The registry describes a completed, randomized, triple-masked, parallel-group Phase 3 study in people with gout who had an inadequate response to allopurinol. Enrollment was 610. The three listed groups received lesinurad 200 mg plus allopurinol, lesinurad 400 mg plus allopurinol, or placebo plus allopurinol.

The primary endpoint was the proportion with serum urate below 6.0 mg/dL by Month 6 in the Intent-to-Treat Population. The sponsor-reported risk-difference analyses favored each lesinurad combination relative to placebo plus allopurinol, with reported p-values of < 0.001. A simple re-calculation from the posted summary statistics conflicts with those reported estimates; the sponsor’s own analysis takes precedence, and the reason for the discrepancy is not reported in the registry record.

The registry also reports gout-flare results and lists a tophus-resolution outcome without posted results. It reports serious and other adverse-event counts, but the available information does not establish causal attribution. Details on missing-data handling, multiplicity, interim analyses, and the trial’s sample-size justification are not reported in the registry record.