Effectiveness of Pulmozyme in Infants With Cystic Fibrosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness of Pulmozyme in Infants With Cystic Fibrosis (NCT00179998), a randomized phase 2 study. The primary outcome is Chest CT (High Resolution Computed Tomography (HRCT) Score).

2. Clinical Question

This is a question about a measured imaging score, not a direct measure of every aspect of cystic fibrosis or airway mucus clearance. The trial was randomized and quadruple-masked, but the registry record does not identify the groups of people covered by the masking description. The crossover design means participants were assigned to treatment sequences rather than simply to a single treatment for the entire study. How the sequence structure was handled in the primary statistical analysis is not reported in the registry record.

3. Trial Design

The registry record describes a randomized, quadruple-masked, phase 2 crossover trial with enrollment of 24 participants. Its status is completed. The listed start was 2005-01, and primary completion was 2008-10. Nationwide Children's Hospital is named as the sponsor.

Participants were assigned to one of two sequences: nebulized rhDNAse followed by placebo, or placebo followed by rhDNAse. The arm descriptions specify once-daily nebulized treatment. The record does not report the length of each treatment period, the timing of assessments relative to each period, or whether a washout was planned. It also does not explain how the crossover sequence was incorporated into the statistical analysis.

The posted primary summaries list 12 participants for each treatment condition and give mean change in HRCT score with standard deviations. A crossover design generally allows within-participant comparisons, since the same participant may receive both treatments. That potential advantage depends on how the data are collected and analyzed. The posted comparison is an unadjusted comparison of the listed summaries; it does not show a paired, period-adjusted, or sequence-adjusted analysis. Such an analysis is not reported in the registry record.

Quadruple masking indicates that the record labels the study as masked at four levels, but the identities of those masked are not reported in the registry record. Further details of allocation concealment, adherence, participant flow, withdrawals, and the original statistical plan are also not reported in the registry record. These omissions limit how fully the conduct and analysis can be evaluated from the registration information alone.

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.

Initial Period - 6 Months

Crossover Period - 6 Months

Analysis population for the primary outcome, as defined in the registry: Subjects will include children with CF \< 30 months old and never treated with Pulmozyme. Patients available for recruitment will include 12 newly diagnosed children \<30 months old from Nationwide Children's Hospital and 4 from Dayton Children's.

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 Chest CT (High Resolution Computed Tomography (HRCT) Score), measured over 6 months.

The primary endpoint is change in total chest HRCT score from initiation of intervention to 6 months. HRCT is an imaging approach used to characterize structural and other changes in the lungs. The registry describes a modified Maffessanti scoring system, combining airway findings and parenchymal findings across the listed lung sections. Airway components include bronchial wall thickening, bronchiectasis, their extent, and gas trapping. Parenchymal components include airspace disease, ground-glass opacity, and mucous plugging. The total score ranges from 12 to 92, with higher scores indicating greater impairment.

A structured score can turn imaging observations into a measure that can be compared across participants and treatment conditions. Measuring change focuses the outcome on how the score differs from its value at intervention initiation, rather than only on the score at a single assessment. The registry record does not report the individual baseline and follow-up scores, the scoring procedures used to limit reader variability, or the amount of missing imaging data.

The posted mean changes were 3.7 for nebulized rhDNAse and 6.1 for nebulized saline. The contrast is reported as the saline mean minus the rhDNAse mean. Because higher scores indicate greater impairment, the direction of that contrast describes the difference in mean score change, not a direct measure of all possible clinical effects. The score is one imaging endpoint; it does not by itself establish how participants felt, functioned, or experienced symptoms.

7. Results Posted in the Registry

• Nebulized Saline: mean 6.10 versus 3.70 on control; difference 2.40 (95% CI -10.69 to 15.49), standardized effect d = 0.15; z-test p = 0.719.

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.

Antibiotic Treatment Days

• 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:
  • Placebo (Nebulized Saline) Then rhDNAse: mean 36.30 versus 31.70 on control; difference 4.60 (95% CI -13.33 to 22.53), standardized effect d = 0.21; z-test p = 0.615.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Placebo (Nebulized Saline) Then rhDNAse and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists antibiotic-treatment days as the secondary outcome. Its posted summaries and unadjusted comparison do not provide a statistically clear contrast: the reported interval includes zero, and the unadjusted p-value is 0.615. The primary HRCT comparison also has an interval that includes zero and an unadjusted p-value that does not indicate a clear distinction. Considered together, the posted outcomes do not present a consistent basis for a confident claim that the treatment conditions differ.

Antibiotic-treatment days and HRCT score reflect different aspects of the study question. One is a count of treatment days over a 6 month interval, while the other is a structured imaging score. Results on one measure do not automatically confirm or contradict results on the other, because the outcomes may capture different processes and have different variability. The registry record does not report an analysis linking changes in antibiotic use to changes in imaging scores.

Secondary results generally carry less weight than a prespecified primary result when several outcomes or analyses are considered. Looking across multiple outcomes increases the chance that at least one estimate will appear unusual by chance. A multiplicity adjustment or a prespecified hierarchy can help address this concern, but the registry record does not report such a plan. It also does not provide a detailed analysis report for the secondary outcome.

Accordingly, the secondary outcome is most useful as complementary descriptive information, not as independent confirmation of the primary result. Its uncertainty and the lack of reported multiplicity procedures should be considered alongside the crossover-analysis limitations. The registry record does not report additional secondary findings that would allow a broader pattern to be assessed.

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

• Antibiotic Treatment Days

9. Statistical Interpretation

10. Statistical Methods Explained

The posted outcomes are continuous measures summarized by means and standard deviations. A mean describes the average recorded value in a group, while the standard deviation describes the spread of individual observations around that mean. The mean is useful for comparing group averages, but it does not show the full distribution of participant outcomes. When variability is large relative to the sample size, the estimated mean difference can be uncertain.

What does a mean difference represent?

The primary contrast is expressed as the saline mean minus the rhDNAse mean. Its estimate of 2.4 describes the difference between the two posted mean changes in HRCT score. The positive sign indicates that the listed saline mean change is numerically higher. Since the score's higher values indicate greater impairment, the direction can be described in terms of the score; it should not be extended into a broader claim about clinical benefit. The contrast is an unadjusted calculation from the posted summary statistics, not a reported adjusted trial-model estimate.

The secondary contrast uses the same general idea for antibiotic-treatment days, with the posted mean difference of 4.6. The comparison is again an unadjusted calculation from the posted group summaries. Both outcomes therefore describe differences in means, not differences in every participant's experience. They also do not show whether a small number of participants contributed unusually high or low values.

Why does the crossover design matter?

In a parallel-group trial, each participant is assigned to one treatment condition. In a crossover trial, participants are assigned to sequences and can receive more than one condition over time. Measurements from the same participant are usually related. A suitable analysis can use that within-participant structure and may account for treatment period and sequence. This can improve the comparison when the design and data support it, but it also requires appropriate information about treatment timing and the analysis model.

The registry identifies two sequences, but it does not report a paired analysis, a period effect, a sequence effect, a washout, or a model for possible carryover. The simple unadjusted comparisons of the posted means do not incorporate these features. The reported results can be described as contrasts between posted summaries, but the record does not provide enough detail to determine how the intended crossover analysis was conducted.

How should the interval and p-value be read?

A confidence interval is a range calculated by a statistical procedure to represent uncertainty around an estimate. In general, a wider interval indicates less precision, while a narrower interval indicates greater precision, given the method and assumptions. The registry reports intervals for both mean differences, but the confidence level and the method used to construct them are not reported in the registry record. The intervals include zero, so they do not rule out a zero mean difference under the reported calculation. Their span also indicates that materially different effects in either direction remain compatible with the estimates.

A p-value measures how unusual the observed data, or data more extreme, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. The posted p-values are unadjusted. The registry record does not report the test used, the model underlying the p-values, or a trial-specific significance threshold. The planning illustration uses a two-sided significance level of 0.05, but that is not evidence of the original trial's analysis plan.

What do the standard deviations contribute?

Standard deviations communicate participant-level spread, not the precision of the mean by themselves. Precision also depends on how many observations contribute and on the design and analysis. Here, the primary means have standard deviations of 21.1 and 9.5, with 12 participants listed in each group. These summaries indicate appreciable variability in the primary measure, especially relative to the mean changes. In a crossover study, the variability of within-participant differences would also be relevant, but it is not reported in the registry record.

The posted comparison lists standard errors for the individual group means as 6.091 and 2.742. A standard error describes uncertainty in an estimated mean, under the calculation used; it is not the spread among individual participants. The record does not explain the standard-error method. Those quantities should therefore be interpreted as posted summaries rather than as proof that a particular crossover or repeated-measures model was fitted.

Over-dispersion is a general concern when observations vary more than a statistical model expects. In a continuous-outcome setting, greater variability makes estimates less precise than they would be under a lower-variability model. In this trial, the primary standard deviations differ between the two listed conditions. That makes assumptions about common variability relevant to a simple comparison. It does not by itself identify why the variability differs, and the registry record does not report an analysis of variance assumptions or a robust alternative.

Finally, a posted aggregate mean does not reveal the distribution of individual changes, whether there were outliers, or whether results were influenced by missing observations. Participant-level data and analysis details are not reported in the registry record. Interpretation should therefore stay close to the estimates, their intervals, and the design limitations rather than treating a single p-value as a complete account of the evidence.

11. Confidence Intervals and Precision

The primary mean difference is 2.4, and the reported interval runs from -10.69 to 15.49. This range includes zero and extends to both negative and positive differences. In practical statistical terms, the estimate is not precise enough to confine the plausible contrast to one direction. The interval is also broad relative to the point estimate, so the central estimate should not be treated as a highly exact description of the difference.

The secondary mean difference is 4.6, with a reported interval from -13.33 to 22.53. It likewise includes zero and spans differences in either direction. The registry record does not state the confidence level or interval-construction method, so those details cannot be independently assessed from the record. A confidence interval generally describes uncertainty around an estimate under a statistical procedure; it is not a guarantee that the true value lies within the particular interval.

Precision depends on more than the number of participants. Variability, the relationship between repeated measurements, and the analysis model can all matter. The registry lists 12 participants per treatment condition, but does not report the variability of within-participant contrasts for the crossover design. The reported standard deviations describe the listed group summaries, and do not replace that information. The record also does not describe how missing observations, if any, were handled.

These intervals do not establish equivalence or rule out potentially meaningful differences. Such conclusions would need a prespecified margin and an appropriate design and analysis, which are not reported in the registry record. The appropriate reading is that the estimates have substantial uncertainty and that the posted results alone do not sharply distinguish among several possible underlying differences.

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 sample-size illustrations are planning calculations based on the observed effect, not the trial's original design assumptions. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row considers an effect equal to the stated fraction of the observed effect. The original trial's sample-size justification and design assumptions are not reported in the registry record.

The figures are participants per arm, not total participants or total events. The 80% power column gives the approximate number of participants per arm that the planning calculation indicates would be needed to have an 80% chance of detecting the assumed effect under those assumptions. The 90% power column expresses the corresponding planning target for a 90% chance. These are prospective illustrations, not observed power.

The rows that plan for a smaller fraction of the observed effect require more participants per arm. This is a general feature of power calculations: smaller differences are harder to distinguish from random variation, so larger samples are usually needed under otherwise similar assumptions. The figures are especially sensitive to the estimated effect used. When that estimate comes from a small trial, it can be unstable and may not be a dependable planning value for a future study.

The calculations also use a simplified two-arm framework. The trial itself is described as a crossover, and the registry record does not report the assumptions or model from its original design. The planning illustrations therefore should not be taken as a reconstruction of the actual trial protocol or as a tailored calculation for a future crossover study. Their meaning is limited to the stated planning assumptions and the effect fractions used.

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 = 2.400; pooled standard deviation σ = 16.362.
2. n = 2 × (1.96 + 0.842)² × 16.362² / 2.400² = 729.6, rounded up to 730 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 <- 2.4                      # observed difference in means
sigma <- 16.3624570282094                     # 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(179998)
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 = 730 (80% power), 977 (90% power)
 75% of observed effect: n per arm = 1,298 (80% power), 1,737 (90% power)
 50% of observed effect: n per arm = 2,919 (80% power), 3,908 (90% power)
power.t.test: 730.6 
Simulated power at n = 730 per arm: 0.803 (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 lists one primary endpoint and one secondary outcome. It does not report a multiplicity strategy, such as an adjustment across outcomes or a prespecified order for testing them. When several outcomes are examined, the chance of finding a seemingly notable result by chance can increase. This general concern is one reason secondary findings are usually interpreted with more caution than a primary analysis specified in advance.

The record reports no analyses in its analysis listing. It provides posted summary statistics and simple unadjusted comparisons, but does not identify a prespecified statistical analysis plan, the primary model, or the method used to obtain the reported p-values and intervals. The original sample-size justification, trial-specific significance threshold, and planned handling of repeated measures are not reported in the registry record.

Missing-data handling is also not reported in the registry record. It does not state how many participants completed each treatment period, whether any outcome assessments were unavailable, how incomplete records were handled, or whether any imputation method was used. Without those details, it is not possible to assess whether the posted summaries include all randomized participants or whether missing observations could affect the estimates.

The analysis population is not specified. The registry record does not state whether results were based on all randomized participants, participants who completed both periods, or another defined group. Nor does it report an intention-to-treat or per-protocol analysis. Those distinctions can matter, particularly in a crossover trial where completion of both treatment periods and the handling of sequence and period are relevant.

These omissions do not establish that the analyses were inappropriate; they mean that the registry record does not allow those aspects to be evaluated. The posted comparisons should be read as the available unadjusted summaries, not as a complete account of a prespecified crossover analysis or of all analysis decisions.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: wheezing (8.3%).

The adverse-event record separates participants by treatment sequence. In the sequence described as nebulized rhDNAse then placebo, 1 of 12 participants is listed as having a serious adverse event. In the sequence described as placebo then rhDNAse, 0 of 12 are listed as having a serious adverse event. Wheezing is listed among the top serious-event terms at 8.3%.

These figures are counts for the sequence groups, not a clear attribution of events to one treatment exposure. Because participants could receive both conditions in a crossover, the registry summaries do not show when each event occurred in relation to treatment, or whether the event was considered related to treatment. The record does not report further event-level detail or a statistical comparison of serious adverse events.

Other adverse events are listed for 11 of 12 participants in each sequence group. Death counts are not reported in the registry record. These summaries are descriptive and based on small groups; they do not establish that the safety profiles are the same or different. Interpretation is limited by the absence of event timing, severity detail beyond the serious-event designation, attribution, and a reported safety analysis.

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

The posted primary result describes a mean difference in change in HRCT score between the listed treatment conditions. The estimate is 2.4, with a reported interval from -10.69 to 15.49. The interval includes zero, and the unadjusted p-value is 0.719. These data do not provide a precise estimate of the contrast and do not establish a clear difference between the posted means.

That does not mean the treatments are equivalent. A result that does not clearly distinguish two means may reflect uncertainty as well as a small underlying difference. Establishing equivalence would require a prespecified range of differences considered unimportant and a suitable analysis. The registry record does not report an equivalence margin or an equivalence analysis. Nor does the result prove that there is no difference.

The imaging score has a defined range and direction, with higher scores indicating greater impairment. It is nevertheless one measure among many possible ways to describe the condition. A score change does not directly summarize every symptom, daily function, or other outcome. The registry also lists antibiotic-treatment days, but its posted comparison is uncertain and should be regarded as complementary rather than as confirmation of the imaging result.

Interpretation is further constrained by the crossover design and the lack of a reported analysis accounting for within-participant comparisons, treatment period, or sequence. The posted unadjusted contrasts are informative descriptions of the available summaries, but the record does not establish that they represent a complete analysis of the trial's crossover structure. Missing-data handling and the analysis population are also not reported.

Overall, the registry record offers estimates that are compatible with a range of possible differences. It does not support a definitive treatment-effect conclusion from these summaries alone. This statistical interpretation is not medical advice and should not be extended beyond the measured outcomes, study population, and information documented in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically instructive because it pairs a crossover design with posted comparisons that are simple contrasts of group summaries. In a crossover, the same participants may contribute observations under more than one condition. That structure can be important to precision and interpretation, but evaluating it requires details about periods, sequence, repeated measurements, and the analysis model. Those details are not reported in the registry record.

The example also shows why a point estimate should be read together with its interval and the underlying variability. The primary estimate is 2.4, but the reported interval ranges from -10.69 to 15.49. The standard deviations differ between the listed conditions, and the group counts are limited. A single central estimate cannot convey that uncertainty by itself.

Another useful lesson is the distinction between a non-significant result and evidence of no effect. The primary interval includes zero, but also includes differences in either direction. Without a prespecified equivalence margin, the posted result cannot demonstrate equivalence. The same caution applies when interpreting the secondary outcome.

Finally, the planning illustrations are not the trial's original sample-size justification and are not observed power. They show how planned sample size depends on the effect assumed and the stated calculation assumptions. Together, these points make the record a useful example of how design, analysis reporting, precision, and planning assumptions shape what can be concluded from clinical trial summaries.

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 posted primary comparison does not document an analysis tailored to the crossover design. Although participants were assigned to treatment sequences, the reported contrast is an unadjusted comparison of the listed summaries. The record does not report a paired analysis, period or sequence effects, or a washout. This makes it difficult to determine how well the comparison reflects the design.

The sample is limited to 24 enrolled participants, with 12 listed in each condition. The primary standard deviations show substantial spread, and the reported interval is wide. The registry does not provide participant-level data, baseline and follow-up summaries separately, or the variability of within-participant changes. These gaps restrict assessment of both the estimate and its precision.

Recruitment was described as involving young children with cystic fibrosis who were less than 30 months old and had never received Pulmozyme. The record therefore does not establish how results might apply to other ages, treatment histories, or populations. It also does not report participant flow, adherence, withdrawals, or outcome completion by treatment period.

Analysis details are sparse. The original statistical plan, sample-size justification, handling of missing data, analysis population, interval method, and multiplicity approach are not reported in the registry record. The masking description does not identify which groups were masked. The posted secondary outcome adds information, but its analysis is also unadjusted and the record reports no analyses in its analysis listing.

Finally, adverse-event summaries are reported by sequence and do not establish treatment attribution or event timing. The small group counts and limited event detail constrain safety interpretation. These limitations concern what can be evaluated from the registry record; they do not, by themselves, establish that any unreported procedure was or was not performed.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Effectiveness of Pulmozyme in Infants With Cystic Fibrosis — NCT00179998.
• Registry record last updated 2019-05-09; status last verified 2019-04.
• Results first posted 2019-05-09.
• 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

The registry record describes a completed, randomized, quadruple-masked phase 2 crossover trial sponsored by Nationwide Children's Hospital. Enrollment was 24. The listed start was 2005-01, and primary completion was 2008-10. The study concerned children with cystic fibrosis who were less than 30 months old and had never been treated with Pulmozyme.

Participants were assigned to sequences involving once-daily nebulized rhDNAse and nebulized saline placebo. The primary outcome was change in total HRCT score at 6 months. The posted mean difference was 2.4, with a reported interval from -10.69 to 15.49 and an unadjusted p-value of 0.719. Antibiotic-treatment days were listed as a secondary outcome.

The registry record does not report the original sample-size justification, a detailed crossover analysis, missing-data procedures, the analysis population, or a multiplicity plan. The posted estimates should therefore be interpreted as uncertain unadjusted summaries rather than as a complete account of the trial's analysis.