Palifermin in Lessening Oral Mucositis in Patients Undergoing Radiation Therapy and Chemotherapy for Locally Advanced Head and Neck Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Palifermin in Lessening Oral Mucositis in Patients Undergoing Radiation Therapy and Chemotherapy for Locally Advanced Head and Neck Cancer (NCT00360971), a randomized phase 3 study. The primary outcome is Duration of Oral Mucositis as Measured in Terms of Days.

2. Clinical Question

3. Trial Design

This was a randomized, phase III, parallel-group study comparing palifermin with placebo in patients receiving radiation therapy and concurrent cisplatin for locally advanced head and neck cancer. The registry describes the study as double-blind in its official title and reports triple masking in its design information. It does not identify which parties were masked, so the precise masking arrangements are not reported in the registry record.

The treatment arms shared radiation therapy and cisplatin; the assigned study treatment was palifermin or placebo. Neck dissection was planned afterward for selected or indicated patients, not described as a procedure received by every participant. The study’s stated focus was the reduction of oral mucositis, with the primary outcome measuring its duration during the acute period.

The registry lists enrollment of 21 and a terminated status. It records a start of 2006-07 and primary completion of 2008-05. The reason for termination, the date of termination, and whether the termination was related to recruitment, safety, funding, or another cause are not reported in the registry record. The record does not establish that the trial stopped because of any particular result.

Although the trial was designated phase III, the posted primary outcome description says statistical testing was not done because of the small sample size. The posted arm summaries therefore need to be read in the context of the limited enrollment and the absence of reported sponsor testing. The registry record does not provide a detailed account of trial conduct, protocol deviations, or treatment adherence.

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: All eligible patients.

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.

Population: All eligible patients.

6. Primary Endpoint

The registry lists the primary outcome as Duration of Oral Mucositis as Measured in Terms of Days, measured over Twice-weekly from start of treatment up to 15 weeks after the start of treatment..

The primary endpoint was the duration of oral mucositis, measured in days, for World Health Organization grade 3 or 4 mucositis during the acute period. The acute period was defined as 105 days, or 15 weeks, from the start of treatment. Duration ran from the onset of grade 3 or 4 mucositis until a report of grade 2 or lower after the last grade 3 or 4 report. Patients whose mucositis remained grade 0 to 2 had a duration of zero.

This outcome captures how long severe mucositis was present rather than only whether severe mucositis occurred. A duration measure can therefore reflect both the onset and the persistence of severe symptoms. The registry specifies a mean and standard deviation for the endpoint, making it a continuous measure expressed in days. The reported time frame was twice-weekly assessment from treatment start through 15 weeks after treatment began.

Duration was used to address the study’s stated question about reducing oral mucositis burden during treatment. It complements an outcome that counts patients with severe mucositis: a count records occurrence, while duration describes how long severe mucositis continued. The registry record does not explain why this endpoint was selected over other possible measures, nor does it report the degree of missing endpoint data or the handling of incomplete duration assessments.

7. Results Posted in the Registry

• Palifermin: mean 13.00 versus 32.00 on control; difference -19.00 (95% CI -39.15 to 1.15), standardized effect d = -0.81; z-test p = 0.065.

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.

Number of Patients With Grade 3 or 4 Mucositis as Measured by the World Heath Organization (WHO) Scale

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Palifermin: 36.4% (4/11) versus 80.0% (8/10) on control; risk difference -43.6 percentage points (95% CI -81.4 to -5.9), risk ratio 0.45 (0.20–1.05); unadjusted two-proportion z-test p = 0.044.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Palifermin than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Time to Onset of Grade 3 or 4 Oral Mucositis as Measured by the World Heath Organization (WHO) Scale

• 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:
  • Palifermin: mean 41.00 versus 48.00 on control; difference -7.00 (95% CI -14.14 to 0.14), standardized effect d = -0.86; z-test p = 0.055.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Palifermin and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes offer context for the primary duration result. The posted pattern is directionally consistent in that fewer participants in the palifermin arm were recorded with grade 3 or 4 mucositis, and the mean time to onset was earlier in the placebo arm. These are different aspects of mucositis: occurrence asks whether severe mucositis was recorded, while onset timing asks when it first appeared. Neither measure is identical to the primary endpoint, which concerns how long severe mucositis persisted.

The secondary comparisons do not settle the primary question. The occurrence outcome has an unadjusted recalculated p-value of 0.044, while the onset comparison has an unadjusted p-value of 0.055. The primary duration comparison has a p-value of 0.065. These figures are simple recalculations rather than sponsor-reported tests, and the registry lists no reported secondary analyses. They should be interpreted alongside the small arm sizes and the uncertainty in the estimates, rather than as a set of independent confirmations.

Multiple secondary outcomes create an interpretation problem when each is examined separately. Even if no real treatment differences existed, considering many outcomes can increase the chance that one appears noteworthy by chance. The registry does not report a multiplicity adjustment or a hierarchy that would identify which secondary measures were confirmatory. The outcomes include mucositis occurrence and onset, as well as survival and second primary tumor measures, but the record does not provide posted analyses for all of those listed outcomes.

Overall, the secondary pattern can support a descriptive account of what was observed, but it carries less weight than a prespecified, sponsor-reported analysis with a stated multiplicity plan. It does not overcome the primary outcome’s wide interval or the record’s statement that formal testing was not performed. Nor can it establish a broader effect on outcomes for which no analysis is posted.

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

• Number of Patients With Grade 3 or 4 Mucositis as Measured by the World Heath Organization (WHO) Scale
• Time to Onset of Grade 3 or 4 Oral Mucositis as Measured by the World Heath Organization (WHO) Scale
• Overall Survival
• Progression-free Survival
• Time to Second Primary Tumor

9. Statistical Interpretation

10. Statistical Methods Explained

The primary measure is continuous: each participant’s mucositis duration is recorded in days, and the arm summaries use means and standard deviations. A mean describes the average duration in an arm; a standard deviation describes how dispersed individual durations are around that average. A substantial standard deviation relative to the mean difference signals that participants’ outcomes varied considerably within the arms. The arm summaries alone do not show the full distribution or whether the data were skewed.

What does the mean difference represent?

The recalculated mean difference is expressed as palifermin minus placebo. A negative value therefore means the posted average duration is shorter in the palifermin arm. The estimate of -19.0 days is a direct unadjusted comparison of the arm means. It does not account for covariates, stratification, repeated assessments, or other features of the trial design. The registry record does not report a sponsor-adjusted estimate, so the recalculation is useful for describing the posted summaries but cannot stand in for an analysis plan or sponsor analysis.

How should the confidence interval be read?

A confidence interval gives a range of values compatible with the data under the method used to calculate it. It communicates uncertainty around the estimated mean difference, rather than the range of individual patient outcomes. For the primary outcome, the interval extends from -39.15 to 1.15 days and includes zero, the value corresponding to no difference between arm means. Its width reflects limited precision. It does not mean that every value in the interval is equally likely, and it does not prove that the true difference lies within the interval.

What does the p-value say?

The unadjusted recalculated p-value of 0.065 describes how unusual a result at least as incompatible with no difference would be under the statistical assumptions of the test, if there were in fact no difference. It is not the probability that the null hypothesis is true, nor does it measure the probability that the result is due to chance. The stated alpha in the primary outcome design description is 0.05. The recalculated p-value is above that threshold, but the registry record says formal statistical testing was not done. The recalculated p-value should therefore not be presented as an official sponsor finding.

Why does over-dispersion matter for a count outcome?

The secondary outcome counting participants with grade 3 or 4 mucositis is binary at the participant level: each person either met the outcome definition or did not. A count or proportion summarizes how often the event occurred, but the observed proportion can be unstable when the arm groups are small. In broader settings, over-dispersion means that variability exceeds what a simple model assumes. It can make standard errors too small and confidence intervals too narrow if a model fails to account for extra variability. The registry record does not report a model-based analysis of this binary outcome, so no claim about over-dispersion handling can be made for this trial.

What was stated about the original primary design?

The primary outcome text says the study required 298 patients to detect a reduction in mean duration of at least 9 days from 29 days on placebo, with a standard deviation of 23 days, using a two-sided t-test, 90% power, and alpha of 0.05. These are the design assumptions recorded for the primary endpoint. The registry does not provide the full calculation, whether any allowance for attrition was included, or whether the assumptions changed during the trial. The listed enrollment is 21, and the record says testing was not done because of the small sample size.

What can be inferred from the secondary analyses?

The secondary outcome results include simple unadjusted recalculations. The registry lists no reported analyses for the posted secondary outcomes. Thus, the recalculated comparisons do not document prespecified sponsor tests, adjustment for multiple comparisons, or a complete analysis strategy. The estimates can describe patterns in the posted results, but any nominal p-values should be treated cautiously. In particular, a p-value just below a conventional threshold does not establish a robust finding when several outcomes are considered and the record gives no multiplicity plan.

In general, clinical trial analyses also need clear definitions of the analysis population, missing-data approach, and handling of participants who discontinue or do not follow assigned treatment. These features can affect both estimates and uncertainty. They are not detailed in the registry record for the posted results. No assumption about imputation, censoring, or an intention-to-treat analysis should be made from the arm summaries alone.

11. Confidence Intervals and Precision

The primary mean difference is -19.0 days, and its 95% confidence interval runs from -39.15 to 1.15 days. Because this interval includes zero, the posted primary summaries are compatible with no difference as well as with a sizable reduction in duration and a small increase. The interval is wide relative to the point estimate, which signals limited precision. Its upper end is close to zero, but the interval as a whole does not pin down a narrow range of plausible effects.

The arm standard deviations are 24.0 days for placebo and 23.0 days for palifermin. Those spreads indicate substantial variation in duration among participants relative to the size of the arm mean difference. The registry record gives no individual-level distribution, so the mean and standard deviation cannot show whether a few long durations influenced the average or how outcomes were distributed across participants.

The small posted arm sizes contribute to uncertainty. The trial enrollment is 21, and the arm summaries list 10 participants for placebo and 11 for palifermin. The confidence interval describes sampling uncertainty under the recalculation method, not all potential sources of uncertainty, including missing data, outcome measurement, or departures from the statistical assumptions.

The interval and p-value are recalculated from the posted summaries, not reported sponsor analyses. The registry says statistical testing was not done due to the small sample size. Accordingly, the confidence interval is a descriptive aid for understanding the precision of the observed contrast; it should not be read as a formal sponsor conclusion. The record does not report a more precise adjusted interval or a sensitivity analysis that could address uncertainty from analysis choices.

12. Planning a Similar Trial: Sample Size

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

The planning figures are illustrations based on the observed effect, not the trial’s original design calculation. For the continuous and binary outcomes listed in these planning entries, each figure means participants per arm. The stated convention for time-to-event planning entries is total events; those are not the relevant units for these listed outcome calculations.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect: 100%, 75%, or 50%. These are planning scenarios, not predictions of what a future study will observe. The primary outcome’s original design description separately states a target of 298 patients under its own assumptions.

The 80% power column gives the participants per arm estimated to provide an 80% chance of detecting the specified effect if that effect were the true one and the stated assumptions held. The 90% power column gives the corresponding per-arm planning figure for a higher chance of detection. Greater planned power requires more participants under the same assumptions.

The entries for smaller fractions of the observed effect call for more participants per arm. That is the usual relationship: smaller effects are harder to distinguish from random variation, so a larger study is generally needed to detect them at a chosen power and significance level. The curve presents the same general planning relationship visually; it does not describe observed outcomes or change the assumptions behind the figures. These calculations are not observed power.

13. How the Sample Size Is Derived

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

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -19.000; pooled standard deviation σ = 23.479.
2. n = 2 × (1.96 + 0.842)² × 23.479² / -19.000² = 24.0, rounded up to 24 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 <- -19                      # observed difference in means
sigma <- 23.4789939710955                     # 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(360971)
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 = 24 (80% power), 33 (90% power)
 75% of observed effect: n per arm = 43 (80% power), 58 (90% power)
 50% of observed effect: n per arm = 96 (80% power), 129 (90% power)
power.t.test: 25 
Simulated power at n = 24 per arm: 0.784 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and multiple secondary outcomes, including mucositis occurrence, time to onset, overall survival, progression-free survival, and time to second primary tumor. It does not report a multiplicity strategy. There is no posted hierarchy indicating which secondary outcome, if any, was intended to be confirmatory, and no reported adjustment for the number of comparisons. As a result, the unadjusted secondary p-values should not be treated as if they came from a single prespecified test.

The record says the primary outcome was not statistically tested because of the small sample size. It also lists no reported analyses for the secondary outcomes. The unadjusted comparisons discussed for posted summaries are recalculations and should not be confused with sponsor analyses or with a documented analysis plan. The registry record does not report interim analyses, stopping boundaries, or an alpha-spending approach. Nothing about interim monitoring or the termination decision should be inferred from their absence in the record.

The analysis population is described for the primary outcome as all eligible patients. The record does not clarify whether this corresponds to an intention-to-treat population, whether all randomized participants were included in each outcome analysis, or how participants who did not meet eligibility criteria after randomization were handled. It also does not report a per-protocol or safety population definition for efficacy analyses.

Missing-data methods are not reported in the registry record. The primary assessment was planned twice-weekly through 15 weeks after treatment began, but the posted results do not describe missing assessments, withdrawal, censoring, imputation, or sensitivity analyses. These details matter because incomplete observations can affect an endpoint based on onset and resolution over time. The results therefore cannot be assumed to be complete-case, imputed, or otherwise handled in any particular way.

These gaps limit the ability to evaluate how robust the estimates are to analysis choices. They do not establish that the study mishandled multiplicity or missing observations; they mean the registry record does not document the relevant methods. Without a reported protocol analysis plan and results, the unadjusted estimates are best treated as descriptive evidence rather than definitive inferential findings.

15. 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% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: mucositis (80.0%), dehydration (30.0%), weight decreased (27.3%), nausea (20.0%), anorexia (20.0%).

The registry reports serious adverse events for each arm as the number of patients at risk and the number affected. For placebo, 8 of 10 patients were recorded as affected; for palifermin, 5 of 11 were recorded as affected. The other adverse-event category lists 9 of 10 patients affected in the placebo arm and 11 of 11 in the palifermin arm. These are patient counts within the posted categories, not a comparison adjusted for differences in exposure or follow-up.

The listed serious-event terms include mucositis at 80.0%, dehydration at 30.0%, weight decreased at 27.3%, nausea at 20.0%, anorexia at 20.0%, and dry mouth at 10.0%. The record does not identify these term percentages as arm-specific in the listed terms, so they should not be assigned to an arm. The deaths field is not populated; deaths are not reported in the registry record.

These figures provide a descriptive safety account, not a causal comparison. The small arm sizes, absence of a reported exposure-adjusted analysis, and lack of detail about event timing and severity limit interpretation. The record does not establish whether an event was caused by the study treatment.

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

The results show lower posted arm averages for duration of severe oral mucositis in the palifermin arm than in the placebo arm. The unadjusted recalculated mean difference is -19.0 days, but its 95% confidence interval extends from -39.15 to 1.15 days and includes no difference. The registry record explicitly states that statistical testing was not done because of the small sample size. The numerical contrast is therefore a descriptive signal with substantial uncertainty, not a definitive efficacy conclusion.

The secondary summaries show fewer recorded cases of grade 3 or 4 mucositis in the palifermin arm and a difference in mean time to onset. These secondary comparisons are also unadjusted recalculations, and the registry lists no reported analyses for them. Their interpretation is limited by the small groups, the uncertainty in the estimates, and the absence of a reported multiplicity approach. They should not be used to convert an inconclusive primary result into a confirmatory one.

The trial does not establish that palifermin does or does not reduce mucositis. A point estimate describes the observed difference, while its interval describes how imprecise that estimate is under the recalculation method. Neither the point estimate nor the p-value alone answers whether a clinically important effect is present. The registry record does not define a threshold for clinical importance for the primary outcome.

The record also does not show that the trial’s termination was related to efficacy, safety, recruitment, or any other specific reason. Its reported phase III designation does not overcome the limitations of the small enrollment and lack of sponsor statistical testing. The posted findings should be interpreted only within this trial’s treatment setting and recorded outcomes; they do not establish effects for other patients, regimens, or settings.

17. Why This Trial Matters Statistically

This study illustrates the difference between a trial’s design label and the amount of information its posted results contain. The record identifies a randomized phase III study, but enrollment was 21 and the primary outcome description says testing was not performed because of the small sample size. A large point estimate can still be imprecise when the data are limited, and this trial’s primary confidence interval is wide and includes no difference.

It also shows why the endpoint definition matters. Counting whether severe mucositis occurred and measuring how long it lasted answer related but distinct questions. The primary endpoint describes duration, while the secondary occurrence measure describes the number of participants reaching the severe grade threshold. A reader should not treat those measures as interchangeable or assume that one confirms the other.

The record provides enough information to describe arm-level means, standard deviations, counts, and simple unadjusted comparisons. At the same time, it does not report sponsor statistical analyses, a multiplicity plan, detailed missing-data handling, or the reason for termination. This contrast is important for statistical interpretation: numerical results can be informative without supporting a firm inferential conclusion.

Finally, the stated original design target and the later enrollment make precision a central concern. The design description refers to 298 patients, whereas the posted enrollment is 21. That gap helps readers understand why the estimated effects remain uncertain, without suggesting what a larger trial would have found. The record is a useful example of keeping observed summaries, planning assumptions, and formal trial conclusions distinct.

18. 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 foremost limitation specific to this study is the small enrollment relative to the target described in the primary outcome text. The record lists enrollment of 21, compared with a stated requirement of 298 for the planned primary contrast. Small groups leave the means and event counts vulnerable to random variation, and the primary interval is broad. The trial’s phase III designation does not remove this limitation.

The registry identifies the study as terminated but does not report why. Without a reason or a detailed account of study conduct, readers cannot determine whether termination affected recruitment, follow-up, outcome completeness, or the planned analyses. No causal explanation for termination can be inferred from the status alone.

The registry reports that statistical testing was not done for the primary endpoint and lists no reported analyses for the secondary outcomes. The displayed comparisons are unadjusted recalculations from arm summaries. The record does not provide an analysis plan, adjusted results, or the methods needed to judge whether the recalculations match the sponsor’s intended approach.

Other important details are also absent from the posted results: the extent and handling of missing assessments, the exact analysis populations, adherence to assigned treatment, protocol deviations, and a multiplicity strategy. The record does not give individual-level distributions, which limits assessment of assumptions behind mean-based comparisons. It also does not identify the parties covered by triple masking.

These are limitations of what can be established from the registry record; they do not prove that a specific bias occurred or that unreported procedures were not used. They mean that interpretation must remain narrow and that the posted results cannot support a complete evaluation of trial conduct or analysis robustness.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Palifermin in Lessening Oral Mucositis in Patients Undergoing Radiation Therapy and Chemotherapy for Locally Advanced Head and Neck Cancer — NCT00360971.
• Registry record last updated 2017-12-26; status last verified 2017-11.
• Results first posted 2014-05-15.
• 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.

22. Record Summary

NCT00360971 is a randomized, phase III, parallel-group, placebo-controlled study of palifermin alongside radiation therapy and concurrent cisplatin for locally advanced head and neck cancer. The registry describes triple masking and lists the study as terminated. Enrollment is 21, with a start of 2006-07 and primary completion of 2008-05.

The primary endpoint was duration of grade 3 or 4 oral mucositis during the acute period, measured in days. The posted arm means were 32.0 days for placebo and 13.0 days for palifermin. An unadjusted recalculation gives a mean difference of -19.0 days with a 95% confidence interval from -39.15 to 1.15. The registry states that statistical testing was not done because of the small sample size.

The secondary summaries and safety counts are descriptive, with no sponsor secondary analyses listed. The reason for termination, multiplicity procedures, missing-data methods, and detailed analysis populations are not reported in the registry record.