Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion (NCT02752633), a na phase 4 study. The primary outcome is Urinary 2,8-dihydroxyadenine Excretion.

2. Clinical Question

The study asked whether urinary 2,8-dihydroxyadenine (DHA) excretion differed during treatment with allopurinol and febuxostat in patients with adenine phosphoribosyltransferase (APRT) deficiency. Each participant was scheduled to receive both medicines in sequence, with washout periods between treatment periods. The endpoint was urinary DHA excretion, measured in mg/24-h at 7, 21 and 42 days.

This question is exploratory: the registry describes the study as an exploratory pilot. The crossover arrangement makes each participant’s observations relevant to both treatments, but it does not by itself establish how the comparison was analyzed. The statistical analysis plan, including any adjustment for period or sequence effects, is not reported in the registry record.

3. Trial Design

The registry describes a Phase 4, exploratory pilot study with an open-label, crossover, single-center and non-randomized design. Enrollment was 9, and the study status is completed. The registry dates the study start to 2013-05 and primary completion to 2015-05. The sponsor is Landspitali University Hospital.

The treatment sequence described in the record begins with a 7 day washout, followed by allopurinol at 400 mg/day for 2 weeks. After another 7 day washout, participants receive febuxostat at 80 mg/day for 2 weeks. The record therefore describes sequential exposure to both medicines, rather than separate concurrent treatment and control groups. Allocation is listed as NA, and masking as none.

This structure has implications for interpretation. Because the treatment order is not randomized, differences between periods may reflect more than treatment alone. Period effects, changes over time, or carryover from an earlier treatment could matter in a crossover study. Washout periods are part of the stated schedule, but the registry does not report evidence that they eliminated carryover. The analysis plan for handling sequence or period effects is also not reported in the registry record.

The primary endpoint is urinary DHA excretion, with median and full range specified at 7, 21 and 42 days. The record does not explain how those assessment days map onto each treatment period, or whether all participants contributed data at every time. It also does not report a sample-size justification or a target enrollment separate from the recorded enrollment. The planning illustration associated with the results is not the trial’s own design or justification.

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:

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 Urinary 2,8-dihydroxyadenine Excretion, measured over 7, 21 and 42 days.

The primary endpoint is urinary 2,8-dihydroxyadenine (DHA) excretion, measured in mg/24-h. The registry specifies a median and full range at 7, 21 and 42 days. This is a measurement of the amount of DHA excreted in urine over a 24-hour period, as described by the endpoint unit.

For a skewed distribution or data with influential extreme values, a median can describe the center without being pulled as strongly by those extremes as a mean may be. The full range conveys the lowest and highest observed values, but it does not show how observations are distributed between those endpoints. These are general properties of the summaries; the registry does not report the actual medians or ranges for this study.

Urinary DHA is relevant to the study question because the trial was designed to compare its excretion during allopurinol and febuxostat treatment in people with APRT deficiency. However, the record does not state why this endpoint was selected beyond identifying it as the primary outcome, nor does it give details of the assay, urine collection procedures, or laboratory quality control. The endpoint values and any treatment comparison are not reported in the registry record. Consequently, the posted endpoint description establishes what was intended to be measured, but not what the observations showed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is summarized by a median and full range. In general, the median is the middle value after observations are ordered and can be useful when data are skewed or contain extreme values. The range gives the minimum and maximum observed values, so it communicates the span of the data but not the concentration of observations within that span. Neither summary alone describes uncertainty in a treatment contrast. The registry does not report the endpoint values, so those summaries cannot be interpreted for this study.

What does a crossover design compare?

In a crossover design, participants receive more than one treatment in sequence, and observations during one treatment period can be compared with observations during another. Because the same people contribute to both periods, an analysis can account for within-person pairing. In general, paired data should not be treated as if every observation came from an unrelated person: observations from the same participant may be correlated. The registry describes the treatments and washouts but does not report whether the analysis used a paired method or how within-person correlation was handled.

Order and period effects are also important in a crossover study. A period effect is a change that occurs over time regardless of treatment. Carryover means that an earlier treatment may continue to influence observations in a later period. A washout is intended to separate treatment periods, but the existence of a washout does not demonstrate that carryover was absent. Here, the record describes the sequence as allopurinol followed by febuxostat, with a 7 day washout between treatment periods. Randomization is not reported; allocation is listed as NA. The statistical approach to sequence, period or carryover effects is not reported in the registry record.

What does the endpoint summary convey?

The unit, mg/24-h, expresses urinary DHA excretion over a 24-hour period. The listed assessment times are 7, 21 and 42 days. Repeated measurements over time can describe how an endpoint changes during treatment, but an analysis needs to account for the dependence among measurements from the same participant. The record does not specify a repeated-measures model, a method for comparing time points, or a single contrast that defines the primary treatment comparison.

Confidence intervals, when reported, generally describe the statistical uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, but interpretation also depends on the endpoint scale and the comparison being estimated. No confidence intervals are reported for this endpoint in the registry record. A p-value, if available, would address compatibility of the data with a specified null model; it would not by itself communicate the size or practical importance of a difference. No endpoint p-value is reported.

How should the planning illustration be read?

The sample-size assumptions describe a planning illustration based on an observed effect, not the trial’s own design. The stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation and an effect defined as a stated fraction of the observed effect. Such calculations are hypothetical planning aids: they ask what sample size would be indicated under selected assumptions. They do not describe the observed study size, establish that the trial was designed around those assumptions, or give observed power. Because the trial is described as a non-randomized crossover study, an equal-allocation comparison between two arms is not a direct description of its treatment sequence. The registry does not report the trial’s sample-size justification.

For count outcomes, over-dispersion is a general concern when variability exceeds what a simple count model assumes. A model that fails to account for it may give misleading standard errors and confidence intervals. The primary endpoint is a continuous urinary excretion measure summarized by a median and range, not a reported count outcome. The registry does not specify a model or variance assumption for the endpoint.

In short, the design and endpoint description permit a general explanation of possible analytic considerations, but the actual methods used to estimate or test a treatment difference are not reported in the registry record. Without those methods and the endpoint values, no recalculated comparison or precision estimate can be described.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one outcome measure and one analysis. That record does not establish whether the endpoint, assessment times or treatment contrast were prespecified in a full statistical analysis plan, nor whether any adjustment for multiple comparisons was used. The listed assessment times are 7, 21 and 42 days. Examining several time points can raise multiplicity concerns when multiple statistical tests are conducted, but the registry does not report how many comparisons were tested or how multiplicity was handled.

Missing-data handling is not reported in the registry record. The record does not say whether all participants completed both treatment periods, whether all endpoint measurements were available, or what method was used if a measurement was missing. It also does not define an analysis population, such as whether analyses included all enrolled participants or only those with observations in both periods. These details matter because exclusions or incomplete follow-up can affect the interpretation of a crossover comparison.

The endpoint is specified as a median and full range, but the registry does not report a statistical analysis plan, a model for repeated observations, or an approach to period and sequence effects. Nor does it state whether any interim analyses were planned or performed. These items are not reported in the registry record and should not be inferred from the endpoint description or the count of recorded analyses.

11. 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.

The registry lists an Allopurinol/Febuxostat Treatment group with 9 at risk for serious adverse events and 0 affected. It also lists 9 at risk for other adverse events and 0 affected, with 0 deaths. No serious adverse event terms are listed.

These figures describe what the registry records for the stated group. They should not be read as proof that either medicine has no risk: a count of zero is an observation in this study, not a guarantee about events outside it. The record does not give event definitions, the observation period for safety reporting, or further details about how events were collected. It also does not present separate safety counts by treatment period. Because both treatments are grouped under one label, these figures cannot be used to compare serious adverse event counts for allopurinol versus febuxostat.

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

The registry record establishes that this completed Phase 4 pilot was designed to examine urinary DHA excretion during sequential treatment with allopurinol and febuxostat in people with APRT deficiency. It specifies the treatment doses, washout schedule and endpoint summaries. It does not report the endpoint results. The record therefore does not show whether urinary DHA excretion was higher, lower or similar during either treatment, or how precisely any difference was estimated.

The study’s open-label and non-randomized sequence is relevant to interpretation. In general, knowledge of treatment and a fixed treatment order can introduce potential sources of bias or make treatment effects difficult to separate from changes over time. A crossover design can support within-participant comparisons, but its strengths depend on suitable analysis and on assumptions about period effects and carryover. The registry does not report the analysis methods needed to evaluate those issues.

The enrollment of 9 and the absence of recorded adverse events do not answer the endpoint question. The enrollment number alone cannot quantify precision, and the safety counts do not establish that adverse events are impossible. Detailed participant characteristics, missing-data handling and safety follow-up are not reported in the registry record.

The record is thus informative about the study’s intended comparison, not its observed efficacy result. It does not support a claim that either treatment does or does not change urinary DHA excretion, and it does not permit a numerical comparison of treatment effects. Any clinical interpretation would require the outcome data and analysis details, neither of which is reported in the registry record.

13. Why This Trial Matters Statistically

This study raises a useful statistical question about how to compare repeated measurements from the same participants. A crossover design can make within-person observations informative because each participant receives both treatments. At the same time, that structure calls for attention to pairing, time trends, treatment order and possible carryover. The registry’s treatment sequence and washouts make these issues relevant, while the absence of a reported analysis plan leaves the analytic choices unclear.

The choice of median and full range also affects how results should be communicated. These summaries can describe the center and span of observations without imposing a mean-based description, but they do not by themselves provide a treatment contrast or its precision. Reporting the numerical summaries alongside a clearly defined contrast and uncertainty estimate would be necessary to understand the observed comparison. Those endpoint values and estimates are not reported in the registry record.

The study also illustrates why planning calculations and trial design should not be conflated. The stated sample-size assumptions are a planning illustration based on an observed effect, whereas the actual study is described as a non-randomized crossover pilot. The planning framework is not evidence of the study’s original sample-size justification, nor is it observed power.

Finally, a completed registry entry can still leave key interpretation questions unanswered. Here, the record identifies the population, schedule and primary endpoint but does not report the endpoint results, missing-data approach or analysis population. Distinguishing what the design intended to measure from what the posted record allows readers to conclude is central to sound statistical interpretation.

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 describes an exploratory pilot with enrollment of 9. It does not report a sample-size justification, target enrollment or participant characteristics, so the context for the recorded enrollment and the representativeness of the participants cannot be evaluated from this record.

The study was open-label and non-randomized, and the stated sequence gives allopurinol before febuxostat. Potential period, order and carryover effects are therefore important considerations, but the registry does not report how they were assessed or addressed. The 7 day washout periods are described; evidence that they were sufficient to prevent carryover is not reported.

The primary endpoint is specified with assessment times and summary measures, but the numerical endpoint results are not reported in the registry record. The timing of those assessments in relation to the treatment periods, completeness of measurement, and analytic handling of repeated observations are also not reported. Without the values and analysis methods, effect size and precision cannot be assessed.

Missing-data handling, analysis population, multiplicity adjustment and the statistical analysis plan are not reported in the registry record. Safety data are grouped across both medicines, and the record does not give separate treatment-period counts or further information about safety observation. These limitations restrict what can be concluded from the registry entry, independently of the study’s intended question.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion — NCT02752633.
• Registry record last updated 2024-04-09; status last verified 2017-12.
• Results first posted 2017-12-27.
• 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

NCT02752633 is a completed Phase 4 exploratory pilot study sponsored by Landspitali University Hospital. The registry lists enrollment of 9 and the condition as adenine phosphoribosyltransferase deficiency. The study is described as open-label, non-randomized, single-center and crossover.

Participants were scheduled to receive allopurinol at 400 mg/day for 2 weeks and then febuxostat at 80 mg/day for 2 weeks, with a 7 day washout before each treatment period. The primary endpoint is urinary 2,8-dihydroxyadenine excretion in mg/24-h, summarized by median and full range at 7, 21 and 42 days.

Numerical endpoint results and details of the statistical analysis are not reported in the registry record. The safety record lists 0 serious adverse events, 0 other adverse events and 0 deaths in the Allopurinol/Febuxostat Treatment group.