Efficacy and Safety Study of Caldolor (Intravenous Ibuprofen) in Hospitalized Adult and Pediatric Burn Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of Caldolor (Intravenous Ibuprofen) in Hospitalized Adult and Pediatric Burn Patients (NCT00606489), a randomized phase 3 study. The primary outcome is Temperature.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, parallel-group trial described in its official title as multicenter, double-blind, and placebo-controlled. The registry lists quadruple masking. It does not explain the specific people or roles covered by that masking label, or the randomization procedure used to assign treatment.

The two listed treatment groups were placebo, described as 250 Milliliters Normal Saline, and 800mg intravenous ibuprofen. The study summary describes dosing every 6 hours for at least 24 hours. The treatment arm descriptions contain no further details. The registry lists an enrollment of 61 and a completed status. That enrollment figure should not be treated as the number contributing to each particular analysis: the outcome summaries list the analyzed group sizes separately.

The trial concerned hospitalized adult and pediatric burn patients. Burns are the listed condition. Other eligibility criteria, recruitment details, participant characteristics, and the reasons participants may not have contributed to the posted outcome are not reported in the registry record. The record gives a start of 2007-11 and primary completion of 2009-05; these dates describe the trial record, not the duration of treatment for an individual participant.

The primary outcome was temperature area under the curve from baseline to hour 24 following treatment initiation. The outcome is reported as a least-squares mean with a standard error for each group. The registry says that analyses were performed for both the Intent to Treat and Efficacy Evaluable populations, but the outcome data presented are for the Intent to Treat population. Results for the Efficacy Evaluable population 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Efficacy analyses were performed on the Intent to Treat (ITT) population and the Efficacy Evaluable Population (EEP). All randomized patients who received at least a partial dose of CTM were included in the ITT analyses. All data below represents the ITT analyses.

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 Temperature, measured over 0 to 24 hours.

The primary endpoint is temperature area under the curve from baseline to hour 24 following treatment initiation. It is expressed in degree Celsius times hours (AUC-T). An area-under-the-curve measure combines temperature observations across a defined time interval into a single summary. In general, this can represent the accumulated temperature profile over that interval, rather than the temperature at just one measurement time.

For this endpoint, a lower value corresponds to a lower accumulated temperature profile over the measured interval, given the endpoint definition. The registry describes the study objective as evaluating fever reduction. AUC-T is relevant to that question because it summarizes temperature over time, while a single reading could miss changes occurring between measurement times. The record does not provide the temperature measurement schedule, the exact calculation procedure, or details of how baseline was incorporated beyond describing the area under the curve from baseline to hour 24.

The reported group values are least-squares means, not labeled as raw arithmetic means. The accompanying standard errors describe uncertainty in those estimated means. The endpoint does not directly measure pain, despite pain appearing in the official trial title, and no pain outcome is posted in the registry record. The record lists one outcome measure and no posted secondary outcomes.

7. Results Posted in the Registry

• 800mg Intravenous Ibuprofen: mean 12.21 versus 18.29 on control; difference -6.08 (95% CI -11.53 to -0.63), standardized effect d = -0.58; z-test p = 0.029.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous endpoint, temperature area under the curve, and presents a least-squares mean for each treatment group. A continuous measure can take a range of numerical values rather than representing a category such as event or no event. A least-squares mean is an estimated group mean from an analysis model. The registry record does not report the model specification or the covariates, if any, used to obtain these estimates. It is therefore not possible to explain what adjustments were made or how the reported estimates relate to unadjusted group averages.

What does the group standard error describe?

A standard error describes the estimated sampling uncertainty of a statistic, in this case each group’s least-squares mean. It is not the spread of individual participants’ temperatures. The reported standard errors are 2.2 for placebo and 1.7 for intravenous ibuprofen. General statistical interpretation: smaller standard errors indicate more precise estimates under the analysis assumptions. The standard error alone does not show the range of individual responses, and it does not provide information about the distribution of temperature measurements. The registry does not report standard deviations or participant-level data for this endpoint.

How should the mean difference be read?

The reported mean difference is -6.08 for intravenous ibuprofen relative to placebo. The comparison uses the group estimates, with the treatment group contrasted against the placebo group. A negative value means the estimated AUC is lower in the intravenous ibuprofen group under that direction of comparison. The unit follows the endpoint: degree Celsius times hours. This is an estimated difference between group means, not a statement that each participant’s temperature changed by that amount.

General statistical interpretation: comparing group means is a way to summarize the difference between treatment groups on a continuous outcome. The result remains subject to uncertainty from sampling and to the assumptions and implementation of the analysis. The model details are not reported in the registry record, so readers cannot assess whether the assumptions of that model were checked or how any deviations were addressed.

What does the confidence interval add?

A confidence interval gives a range of values compatible with the data and the procedure used to construct it, under the statistical assumptions. The posted interval for the mean difference lies below zero. That indicates the reported interval does not include no difference. It also makes clear that the point estimate should not be interpreted as exact: a range of effect sizes remains compatible with the analysis. The registry does not explain the confidence-interval method or state whether it was adjusted for other comparisons.

What does the p-value say?

The unadjusted p-value is 0.029. In general, a p-value describes how unusual data at least as incompatible with a specified null model would be if that model were true, under the analysis assumptions. It is not the probability that the null model is true, nor the probability that the finding occurred by chance. An unadjusted p-value does not account for multiplicity. The registry does not report a multiplicity adjustment, a prespecified decision threshold, or a full statistical analysis plan, so the p-value should be interpreted as the posted unadjusted result rather than as a complete account of all analytic decisions.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when the variability in the data is greater than a statistical model expects. It can make standard errors too small if the analysis does not allow for that extra variation, potentially making confidence intervals too narrow and p-values too small. The endpoint is continuous, and the registry record does not report a model diagnostic or identify over-dispersion as an issue. This concept is therefore relevant as a general reason to examine model assumptions, not as a documented problem in this trial.

What is and is not documented about the analysis?

The outcome description names the Intent to Treat and Efficacy Evaluable populations and states that the posted values are for the Intent to Treat population. The record defines the Intent to Treat population as randomized patients who received at least a partial dose of CTM. It does not provide results for the Efficacy Evaluable population. The registry does not report the least-squares model, handling of missing temperature values, methods for constructing the confidence interval, or whether interim analyses occurred. The analysis entries count is listed as zero, even though the primary outcome summary and comparison are posted; these are separate elements of the registry record.

10. Confidence Intervals and Precision

The mean difference estimate is -6.08 degree Celsius times hours for intravenous ibuprofen relative to placebo. Its confidence interval lies entirely below zero. A confidence interval is useful because it communicates uncertainty around the estimated difference, rather than treating the point estimate as exact. The interval supports a range of possible differences under the method used; it does not show the range of individual participants’ temperatures or responses.

The registry’s reported standard errors are 2.2 for the placebo least-squares mean and 1.7 for the intravenous ibuprofen least-squares mean. These quantify uncertainty in the group estimates, not participant-to-participant variability. The underlying variability of individual AUC measurements is not reported. Nor does the registry describe the confidence-interval construction or the model used to estimate the least-squares means. Those omissions limit independent assessment of how the precision was calculated.

The reported interval excludes zero, and the unadjusted p-value is 0.029. Together, these statistics indicate that the estimated difference is not especially compatible with a no-difference value under the reported analysis, while still leaving uncertainty about the size of the difference. The interval’s upper endpoint is reported with more than three decimal places, so it is not reproduced numerically. No clinical-importance threshold is reported, and statistical precision alone cannot establish whether the estimated difference is important in practice.

The group outcome summaries list 21 participants for placebo and 40 for intravenous ibuprofen. The record does not state how many temperature observations were available within each participant, whether all observations were complete, or how missingness affected the precision. It also does not provide age-specific estimates or precision measures. Thus, the overall interval cannot be used to assess precision for subgroups that are not reported.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design calculations. The registry does not report the trial’s original sample-size assumptions or justification. These planning figures are participants per arm, not total event counts. They assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is set to a stated fraction of the observed effect.

For planning for 100% of the observed effect, the illustration gives 48 participants per arm for 80% power and 64 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 84 participants per arm for 80% power and 113 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 189 participants per arm for 80% power and 253 participants per arm for 90% power.

In plain terms, the 80% power column describes the planned number per arm under these assumptions for a design with an 80% chance of detecting the specified effect at the stated significance level, if that effect and the assumptions hold. The 90% power column uses a higher target chance of detection for the same effect assumption. The figures increase as the target effect becomes smaller: a smaller difference is harder to distinguish from random variation, so planning for it requires more participants under the same assumptions. The sample-size illustrations are not observed power.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -6.080; pooled standard deviation σ = 10.529.
2. n = 2 × (1.96 + 0.842)² × 10.529² / -6.080² = 47.1, rounded up to 48 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
delta <- -6.08                      # observed difference in means
sigma <- 10.5293777883676                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(606489)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 48 (80% power), 64 (90% power)
 75% of observed effect: n per arm = 84 (80% power), 113 (90% power)
 50% of observed effect: n per arm = 189 (80% power), 253 (90% power)
power.t.test: 48.1 
Simulated power at n = 48 per arm: 0.802 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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 record lists one outcome measure and no posted secondary outcomes. It reports a primary outcome comparison and an unadjusted p-value of 0.029. No multiplicity adjustment is reported. The record does not establish whether additional outcomes or analyses were planned but not posted, so the primary comparison should not be treated as proof that no other comparisons were considered.

The outcome description identifies both an Intent to Treat population and an Efficacy Evaluable Population. It defines the Intent to Treat population as all randomized patients who received at least a partial dose of CTM, and states that the data presented are for the Intent to Treat analyses. The registry does not report results for the Efficacy Evaluable Population or explain how that population was defined. The record’s use of the term Intent to Treat alongside the partial-dose criterion should be understood as the registry’s stated definition, rather than replaced with a different definition.

Missing-data handling is not reported in the registry record. In particular, the record does not say whether temperature measurements were missing, how incomplete profiles were handled in the AUC calculation, or whether any imputation method was used. It also does not report sensitivity analyses addressing missing outcomes. These details matter because an AUC estimate depends on measurements across the stated interval and the handling of unavailable observations can affect both estimates and their precision.

The record lists zero analysis entries, although it does contain primary outcome summaries and a comparison. It does not report a full statistical analysis plan, interim analyses, or decision rules. The existence and consequences of any such procedures cannot be inferred from the posted result. Accordingly, the unadjusted significance result should be interpreted with the reported outcome and analysis-population information, while recognizing that the registry record does not document several elements needed to evaluate the wider analysis process.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute respiratory arrest syndrome (9.5%), cardiopulmonary arrest (4.8%), cardiac arrest (4.8%), tachypnoea (4.8%), hypotension (4.8%).

The serious adverse event summary lists 3 affected participants among 21 at risk in the placebo group and 5 among 40 at risk in the 800mg intravenous ibuprofen group. These are counts reported by group. They describe participants with serious adverse events as recorded, not the number of individual serious events, and the registry record does not provide a causal assessment for the treatment groups.

The record also lists other adverse events for 15 participants among 21 at risk in the placebo group and 23 among 40 at risk in the intravenous ibuprofen group. These are presented separately from the serious adverse event figures. The record does not provide further detail in this summary about event severity, timing, duration, or whether participants had more than one event.

The listed serious-event terms include Acute respiratory arrest syndrome, Cardiopulmonary arrest, Cardiac arrest, Tachypnoea, Hypotension, and Severe septic shock, each with a registry percentage. The terms are not assigned to a treatment group in the posted term list, and the denominator for those percentages is not specified in that list. They should not be attributed to either arm from this information alone. Death counts are not reported in the registry record.

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

The posted result describes a difference in temperature AUC over 0 to 24 hours between the two randomized groups. The least-squares mean was 18.29 for placebo and 12.21 for 800mg intravenous ibuprofen. The reported mean difference, with ibuprofen relative to placebo, was -6.08. On this endpoint, that direction indicates a lower estimated accumulated temperature in the ibuprofen group. The confidence interval lies below zero, and the unadjusted p-value is 0.029.

This finding is limited to the temperature endpoint and time interval reported. It does not establish what happened to temperature beyond hour 24, nor does it answer the separate question of pain relief. Pain appears in the official trial title and fever reduction is the stated study objective, but no pain result is posted. The record also does not provide results for secondary clinical outcomes.

The registry result does not establish the clinical importance of the estimated difference because no threshold for an important AUC change is reported. It does not show individual participant responses, explain the range of temperature profiles, or demonstrate that the group estimates apply equally across adults and pediatric patients. Age-specific results are not reported. The record also does not provide the analysis details needed to evaluate model specification or missing-data handling.

The serious adverse event counts and the listed adverse-event terms are descriptive registry data. They do not, by themselves, establish that an event was caused by a study treatment or allow a complete assessment of the safety profile. The term percentages are not linked to a specific arm in the posted list, and death counts are not reported. Overall, the data support a precise description of the posted group comparison, but not broad claims about other outcomes, subgroups, longer-term effects, or treatment causation.

16. Why This Trial Matters Statistically

This trial illustrates why the definition and time window of a clinical endpoint matter. Temperature AUC from baseline to hour 24 condenses a sequence of temperature observations into a continuous summary. That can address accumulated temperature across the interval, but it is different from comparing a single temperature reading or counting fever episodes. Interpretation depends on knowing what was measured and how the summary was constructed; the registry gives the endpoint definition but not the full measurement schedule or calculation procedure.

The report also shows the value of reading an estimate together with its uncertainty. The mean difference of -6.08 gives a direction and a scale on the AUC measure, while the confidence interval and standard errors communicate uncertainty. A p-value alone would not convey the range of plausible effects or the precision of the estimated group means. In this record, the confidence interval lies below zero, while details about the model and interval method remain unavailable.

Population labels are important to interpretation as well. The outcome description identifies two analysis populations but posts data for the Intent to Treat population only. The stated definition includes randomized patients who received at least a partial dose of CTM. Clarifying the population and its definition helps readers understand which participants the outcome summaries represent, while the missing Efficacy Evaluable results prevent comparison of the named populations.

Finally, the registry record distinguishes the primary outcome from safety summaries and planning illustrations. Temperature AUC, adverse-event counts, and hypothetical sample-size requirements answer different questions. Keeping those roles separate avoids treating a statistical result as a complete clinical assessment or mistaking a planning calculation for an observed trial result.

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 gives limited information about how the primary outcome was measured and analyzed. It defines temperature AUC from baseline to hour 24 but does not report the measurement schedule, the calculation procedure, or the statistical model used for the least-squares means. Model covariates, diagnostic checks, and the method for constructing the confidence interval are also not reported in the registry record.

The record does not describe the amount or pattern of missing temperature data, how missing values were handled, or whether incomplete temperature profiles affected inclusion in the AUC analysis. It names the Intent to Treat and Efficacy Evaluable populations, but posts only the Intent to Treat results and does not further define the Efficacy Evaluable population. These omissions limit assessment of how analysis-population choices and missing data may affect the result.

The trial population is described as hospitalized adult and pediatric burn patients, but age distribution, baseline clinical characteristics, burn severity, and subgroup estimates are not reported. The outcome summaries therefore do not show whether the overall result was consistent across adults and pediatric patients or across other participant characteristics. The registry also does not report a clinically important threshold for the AUC measure.

The official title includes fever and pain, while the posted primary outcome concerns temperature and no pain outcome is posted. The safety summary provides group counts and a list of serious-event terms, but does not assign the listed terms to a group or provide the details needed to establish causation. Death counts are not reported. Finally, the registry does not report the trial’s original sample-size justification, multiplicity plan, interim analyses, or full statistical analysis plan. These trial-specific details should not be inferred from the posted result.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of Caldolor (Intravenous Ibuprofen) in Hospitalized Adult and Pediatric Burn Patients — NCT00606489.
• Registry record last updated 2011-08-11; status last verified 2011-07.
• Results first posted 2011-08-11.
• 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

NCT00606489 is a completed phase 3 randomized, parallel-group trial of intravenous ibuprofen versus placebo in hospitalized adult and pediatric burn patients. The official title describes a multicenter, randomized, double-blind, placebo-controlled study; the registry lists quadruple masking. The record lists an enrollment of 61, a start of 2007-11, and primary completion of 2009-05.

The primary outcome was temperature AUC from baseline to hour 24, reported as least-squares means for the Intent to Treat population. The posted mean difference for 800mg intravenous ibuprofen relative to placebo was -6.08, with a confidence interval entirely below zero and an unadjusted p-value of 0.029. The record does not post pain results or secondary outcome results. Safety summaries list serious and other adverse-event counts by group, but the listed serious-event terms are not assigned to an arm.