Rasburicase in Patients at Risk for Tumor Lysis Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rasburicase in Patients at Risk for Tumor Lysis Syndrome (NCT00628628), a randomized phase 2 study. The primary outcome is Number of Participants With Plasma Uric Acid (UA) Response.

2. Clinical Question

The trial’s primary objective was to compare the as-needed schedule with fixed dosing for 5 days in the treatment of patients considered at high or potential risk for tumor lysis syndrome. The registry describes the study as randomized, with parallel groups and no masking. It records 40 participants in each arm for the posted primary outcome.

The main contrast is the difference in the proportion meeting the response definition between Group B, the daily-dose group, and Group A, the single-dose-plus-as-needed group. The registry reports a risk difference of -0.125 for this comparison, with an interval from -0.246 to -0.004 and an unadjusted p-value of 0.048. The posted counts are 34 participants with a response in Group B and 39 in Group A.

The study also set out to evaluate plasma uric acid area under the curve from baseline through 7 days, renal insufficiency, electrolyte abnormalities, safety and immunogenicity, and cost-effectiveness. Results for these secondary objectives are not reported in the registry record. The evidence described in the primary comparison therefore addresses the defined uric acid response outcome, rather than the full set of objectives.

3. Trial Design

This was a phase 2 randomized parallel-group trial sponsored by M.D. Anderson Cancer Center. The registry lists the trial as completed, with enrollment of 82 participants. The recorded start was 2008-01 and primary completion was 2012-05. Masking is listed as none, so the registry describes the trial as unmasked.

Participants were assigned to one of two rasburicase schedules. Group A received .15 mg/kg intravenously over 30 minutes on day 1, with once-daily doses on days 2–5 only as needed. Group B received .15 mg/kg intravenously over 30 minutes daily. The brief summary describes the comparator as fixed dosing for 5 days and identifies it as the standard treatment arm; it describes the as-needed schedule as the investigational arm.

The primary outcome record lists 40 participants in each group. The posted counts meeting the plasma uric acid response definition are 39 in Group A and 34 in Group B. The registry’s total enrollment and the number recorded for each primary-outcome arm are distinct pieces of information; the record does not explain the difference between the enrollment figure and the outcome-arm figures.

The primary outcome timeframe is the first cycle of chemotherapy, up to 5 days. Plasma samples were scheduled at baseline before rasburicase, 4- and 24-hours after rasburicase, and daily during treatment. The registry lists one outcome measure and no posted analyses beyond the primary comparison. Details about the allocation procedure, the trial’s original sample-size justification, planned interim analyses, and a more complete statistical analysis plan are not reported in the registry record.

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: Eighty-two patients were enrolled between February 2008 and February 2010. Two patients withdrew consent and 80 patients were randomized; 40 to the Arm A and 40 to the Arm B.

Overall Study

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 Number of Participants With Plasma Uric Acid (UA) Response, measured over First cycle of chemotherapy, up to 5 days.

The primary endpoint is the number of participants with a plasma uric acid response during the first cycle of chemotherapy, up to 5 days. A response required both normalization of plasma uric acid within 48 hours after study drug began and maintenance within the normal range after the final infusion on day 5. The endpoint therefore reflects a defined pattern over time, rather than a single measurement at one time point.

Plasma uric acid was measured at baseline before rasburicase, at 4 and 24 hours after rasburicase, and daily during treatment. These measurements support assessment of early normalization and whether the level remained in the normal range through the end of the described dosing period. The record does not specify the numeric threshold used for the normal range.

A binary response endpoint presents the outcome as whether each participant did or did not meet the definition. It allows the schedules to be compared by the proportion of participants responding, while the clinical definition determines what counts as success for this particular outcome. It does not, by itself, describe the size or duration of each participant’s change in uric acid, or capture the secondary objectives such as renal insufficiency, electrolyte abnormalities, safety, immunogenicity, and cost-effectiveness.

The registry reports response counts of 39 in Group A and 34 in Group B, with 40 participants recorded in each group. These counts are the basis for the posted comparison. The registry does not report secondary outcome results alongside this primary endpoint.

7. Results Posted in the Registry

• Group B: Daily Dose: 85.0% (34/40) versus 97.5% (39/40) on control; risk difference -12.5 percentage points (95% CI -24.6 to -0.4), risk ratio 0.87 (0.76–1.00); unadjusted two-proportion z-test p = 0.048.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: each participant either met the plasma uric acid response definition or did not. For a binary endpoint, a common way to compare groups is to contrast the proportions of participants with the event. The registry reports a risk difference of -0.125, comparing Group B with Group A. A risk difference is an absolute contrast between proportions on the probability scale. Its sign depends on the order of the groups, so the direction matters: the reported comparison is daily dosing relative to the single-dose-plus-as-needed schedule.

The counts behind this comparison are 34 responses among 40 participants in Group B and 39 among 40 participants in Group A. The registry also lists the corresponding proportions as 0.85 and 0.975, respectively. The reported risk difference is -0.125. These figures are the posted estimates; they are not recalculations. The comparison also includes an unadjusted p-value of 0.048.

What does the risk difference describe?

The risk difference describes an absolute separation between the two observed response proportions. It is distinct from a relative measure, which compares one group’s event probability to the other group’s probability. Absolute and relative measures can offer different perspectives on the same binary outcome, so it is useful to identify which scale is being discussed. For this trial, the risk difference is the stated primary contrast.

The registry additionally lists a risk ratio of 0.872 with limits of 0.758 and 1.002, and an odds ratio of 0.145 with limits of 0.017 and 1.268. A risk ratio compares probabilities, while an odds ratio compares odds. Odds and probabilities are not the same quantity, and an odds ratio should not be described as though it were a risk difference. Each measure has its own interval and scale. These additional measures do not replace the risk-difference estimate.

How should the p-value be read?

The unadjusted p-value of 0.048 measures how incompatible the observed comparison is with a specified null hypothesis under the statistical procedure used. A p-value is not the probability that the null hypothesis is true, nor does it describe the size or clinical importance of the observed contrast. Its interpretation also depends on the analysis plan and on whether multiple outcomes or analyses were considered. The registry does not report a multiplicity adjustment or enough detail to establish whether this was the only planned analysis of the primary endpoint.

“Unadjusted” is important because a p-value can be assessed in a setting with multiple tests, where the chance of at least one small p-value can increase. The registry lists one outcome measure and no posted secondary analyses, but the complete analysis plan and the extent of analyses conducted are not reported in the registry record. The result should therefore be read as the posted unadjusted comparison, not as evidence that multiplicity was formally addressed.

Why does the interval matter?

A confidence interval describes a range of estimates compatible with the data and the method used, under repeated sampling assumptions. It conveys uncertainty about the estimated contrast in a way a single p-value cannot. The risk-difference interval runs from -0.246 to -0.004. This interval places the estimated contrast on the negative side but also shows that values close to zero are compatible with the reported uncertainty. The interval is not a guarantee that the true effect lies within its limits, nor does it account for biases or design limitations that are not represented by the statistical calculation.

Different intervals for different effect measures need not have the same apparent relationship to their null values. For a risk difference, no difference corresponds to zero; for a ratio measure, no relative difference corresponds to one. The listed odds-ratio interval extends from 0.017 to 1.268, and the risk-ratio interval extends to 1.002. Those bounds are interpreted on their own scales and should not be confused with the risk-difference interval.

What can be said about the analysis population?

The registry gives counts of 40 participants in each arm for the primary endpoint, but does not state whether all randomized participants were included, how missing outcome measurements were handled, or whether analysis followed an intention-to-treat principle. These details are not reported in the registry record. The response definition requires measurements across the treatment period, so missing measurements could affect whether a participant can be classified; the record does not describe how such cases were handled.

The registry presents a comparison and its estimates but does not identify the specific statistical test or modeling procedure used to obtain them. It would be inappropriate to infer those methods solely from the reported p-value and interval. The general concepts above explain how binary contrasts, p-values, and intervals are typically interpreted, while the exact analysis procedure for this trial is not reported in the registry record.

10. Confidence Intervals and Precision

The risk-difference estimate for daily dosing relative to the single-dose-plus-as-needed schedule is -0.125. Its reported interval extends from -0.246 to -0.004. This interval communicates uncertainty around the estimated contrast: the compatible values range from a larger negative difference to a value close to no difference. Both interval limits are negative, but the upper limit is near zero, so the estimate is not highly precise about the size of the contrast.

The interval is more informative than the point estimate alone because it shows the range of values that remain compatible with the observed data and the method used. It does not include uncertainty from possible bias, missing data, or departures from the analysis assumptions. Nor does it show whether any value in the range would be clinically important; the registry does not report a threshold for clinical importance.

The registry also lists the risk-ratio estimate as 0.872 with limits of 0.758 and 1.002, and the odds-ratio estimate as 0.145 with limits of 0.017 and 1.268. These are intervals on ratio scales, with a different null value from the risk difference. The odds-ratio interval includes 1, and the upper risk-ratio limit is 1.002. These ratio estimates should be considered separately from the absolute risk-difference interval.

With 40 participants recorded in each arm, the primary contrast is based on a limited number of outcome observations. The registry does not report additional precision measures or subgroup intervals. The posted interval describes precision for the reported comparison, not certainty about other outcomes, populations, or treatment schedules.

11. 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 figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original sample-size calculation. The registry’s original design assumptions and sample-size justification are not reported in the registry record.

The illustrations assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They consider detecting the observed effect, as well as 75% and 50% of the observed effect. For 100% of the observed effect, the illustration gives 80 participants per arm for 80% power and 106 participants per arm for 90% power. For 75% of the observed effect, it gives 118 participants per arm for 80% power and 158 participants per arm for 90% power. For 50% of the observed effect, it gives 213 participants per arm for 80% power and 284 participants per arm for 90% power.

The 80% power column describes the planned chance of detecting the specified effect under those assumptions if that effect is present. The 90% power column uses a higher target chance of detection and therefore calls for more participants for each stated effect. Smaller effects are harder to distinguish from random variation, so the illustrations require more participants per arm as the effect being targeted becomes smaller.

These figures are planning illustrations, not observed power. They do not describe the trial’s actual probability of detecting an effect after the results were known, and they do not establish what sample size the investigators originally intended.

12. 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 = 0.975; treatment proportion p₁ = 0.850; average p̄ = 0.912.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3996 = 0.7832.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3897 = 0.3280.
4. n = (0.7832 + 0.3280)² / (-0.1250)² = 79.0, rounded up to 80 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 <- 0.975                          # control proportion
p1 <- 0.85                          # 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(628628)
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 = 80 (80% power), 106 (90% power)
 75% of observed effect: n per arm = 118 (80% power), 158 (90% power)
 50% of observed effect: n per arm = 213 (80% power), 284 (90% power)
power.prop.test: 79 
Simulated power at n = 80 per arm: 0.840 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists one posted outcome measure and one primary comparison. The study summary nevertheless describes several secondary objectives: plasma uric acid area under the curve from baseline through 7 days, renal insufficiency, electrolyte abnormalities, safety, immunogenicity, and cost-effectiveness. Results for these objectives are not reported in the registry record. No additional secondary analyses are posted.

When multiple outcomes or comparisons are examined, multiplicity can affect how often a result appears statistically notable by chance. Approaches to multiplicity are part of an analysis plan, and the registry does not report a correction procedure or explain how the various objectives were handled statistically. The p-value posted for the primary comparison is explicitly unadjusted. It should be understood as the unadjusted result rather than evidence that a multiplicity strategy was applied.

The registry does not report how missing primary-outcome measurements were handled, whether all randomized participants were analyzed, or whether the analysis followed an intention-to-treat approach. It also does not describe a per-protocol population or other analysis populations. Although 40 participants are recorded in each arm for the primary endpoint, the record does not explain the relation between those arm counts and the overall enrollment of 82.

The endpoint requires assessment of normalization within 48 hours and maintenance of the normal range after the final infusion on day 5. If a participant lacked measurements needed to establish that pattern, the classification could depend on the missing-data rule. That rule is not reported in the registry record. The outcome counts therefore cannot be used to infer how missing measurements were treated or whether any participants were excluded from the analysis.

These omissions limit what can be concluded about the analysis beyond the estimates that are posted. They do not negate the reported primary comparison, but they mean that the detailed analysis populations, handling of missing data, and treatment of the broader set of objectives cannot be independently described from the registry record.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: leukemia (2.5%), lymphoma (2.5%).

The serious adverse event figures list 40 participants at risk in each group. Group A, the single-dose-plus-as-needed group, has 0 participants recorded with a serious adverse event. Group B, the daily-dose group, has 2 participants recorded with a serious adverse event. The registry lists Leukemia and Lymphoma among the serious terms, each at 2.5%.

These figures describe the counts in the registry record. They do not establish that an event was caused by rasburicase, and the record does not provide a causal attribution in the information posted. The listed terms should not be interpreted as a complete description of severity, timing, clinical course, or relationship to treatment.

The registry does not report deaths in these group records; death counts are not reported in the registry record. It also lists 40 participants affected by other adverse events in each group, but the posted summary does not supply the event terms or further details for those counts. Safety interpretation is therefore limited to the serious-event counts and terms recorded, rather than a full characterization of all adverse events.

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

The posted primary results show a higher observed response count in Group A than in Group B: 39 of 40 participants in the single-dose-plus-as-needed group met the response definition, compared with 34 of 40 in the daily-dose group. The reported risk difference, comparing Group B with Group A, is -0.125, with an interval from -0.246 to -0.004 and an unadjusted p-value of 0.048.

These findings describe the comparison for one defined plasma uric acid endpoint in the trial’s recorded participants. They do not establish what would happen in a different population, under a different treatment schedule, or for outcomes beyond the endpoint. The endpoint required early normalization and maintenance through the final infusion on day 5; it is not a broad measure of every clinical consequence associated with tumor lysis syndrome.

The primary result does not answer the secondary questions listed in the study summary. Plasma uric acid area under the curve, renal insufficiency, electrolyte abnormalities, immunogenicity, and cost-effectiveness results are not reported in the registry record. The limited serious adverse event information also does not provide a comprehensive safety comparison or establish causation.

The estimate should be read alongside its interval, which includes values close to zero as well as more negative values. The p-value is unadjusted, and the registry does not report the full statistical plan, missing-data rules, or analysis populations. Those gaps matter when judging how broadly and precisely to interpret the result.

Accordingly, the posted data support a description of the observed response counts and the reported statistical contrast, but not a definitive conclusion about treatment benefit, harm, or comparative clinical value. Such conclusions would require a broader assessment of the trial methods, all relevant outcomes, and the intended clinical context.

16. Why This Trial Matters Statistically

This trial illustrates how the choice of outcome scale affects statistical interpretation. The primary outcome is binary, based on whether a participant met a defined pattern of plasma uric acid normalization. The risk difference communicates the absolute contrast between response proportions, while the registry’s risk ratio and odds ratio express the contrast on relative scales. Keeping the scale and direction explicit helps prevent a relative measure from being mistaken for an absolute change.

It also demonstrates why effect estimates, intervals, and p-values should be read together. The posted risk difference is -0.125, the interval runs from -0.246 to -0.004, and the unadjusted p-value is 0.048. The point estimate gives one summary of the contrast; the interval conveys its uncertainty; and the p-value addresses compatibility with a null hypothesis under the analysis procedure. None of these statistics alone describes clinical importance.

The endpoint definition is another important statistical feature. Response required both normalization within 48 hours and maintenance after the final infusion on day 5. That composite time pattern turns repeated measurements into a single participant-level classification. The resulting binary summary is useful for a direct group comparison, but it does not preserve all information about the timing or magnitude of individual uric acid measurements.

Finally, the registry distinguishes an observed trial result from a planning illustration. The sample-size figures use the observed effect and stated planning assumptions, and they are not observed power or evidence of the trial’s original design target. The incomplete reporting of missing-data handling, analysis populations, and secondary outcomes shows why a numerical comparison is only one part of statistical appraisal.

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.

The registry record leaves important design and analysis details unspecified. The method used to generate or conceal random allocation is not reported in the registry record. The trial is listed as unmasked, but the record does not describe whether outcome assessment or laboratory measurement procedures were blinded. The original sample-size justification and any interim analyses are also not reported in the registry record.

The primary comparison includes 40 participants in each arm, while overall enrollment is recorded as 82. The record does not explain this difference, identify exclusions from the primary analysis, or state whether all randomized participants were analyzed. Missing-data handling and the analysis population are not reported, which is relevant because the response definition depends on measurements at multiple points through day 5.

The registry posts one primary outcome and no secondary analyses, although the study summary names several secondary objectives. Results for plasma uric acid area under the curve, renal insufficiency, electrolyte abnormalities, immunogenicity, and cost-effectiveness are not reported in the registry record. The serious adverse event summary is limited, and the relation of listed events to treatment is not described.

The endpoint is specific to plasma uric acid response during the first chemotherapy cycle, up to 5 days. It does not by itself measure all aspects of tumor lysis syndrome, other clinical outcomes, or longer-term effects. The record also does not provide the numeric normal-range threshold, making the laboratory criterion less fully specified in the posted description.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Rasburicase in Patients at Risk for Tumor Lysis Syndrome — NCT00628628.
• Registry record last updated 2013-08-01; status last verified 2013-05.
• Results first posted 2013-08-01.
• 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

NCT00628628 is a completed randomized phase 2 parallel-group trial sponsored by M.D. Anderson Cancer Center. It enrolled 82 participants at high or potential risk for tumor lysis syndrome and compared an as-needed rasburicase schedule with fixed daily dosing. The registry lists no masking.

The primary outcome was the number of participants meeting a plasma uric acid response definition during the first chemotherapy cycle, up to 5 days. The posted response counts were 39 of 40 in Group A and 34 of 40 in Group B. The reported risk difference for Group B relative to Group A was -0.125, with an interval from -0.246 to -0.004 and an unadjusted p-value of 0.048.

Secondary outcome results, detailed analysis populations, missing-data procedures, and the original sample-size justification are not reported in the registry record. Serious adverse event counts were 0 in Group A and 2 in Group B; the registry lists Leukemia and Lymphoma at 2.5% each.