Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight (NCT00734539), a randomized phase 3 study. The primary outcome is Death or Candidiasis.

2. Clinical Question

The clinical question is about prophylaxis in a narrowly defined, very-low-birthweight neonatal population, not about treatment of an established infection. The registry summary explains the rationale in terms of invasive candidiasis and its serious consequences in premature neonates. It also describes uncertainty about appropriate dosing, safety, and long-term outcomes as motivating a pivotal trial. Those background statements describe the rationale recorded for the study; they are not outcomes measured by the comparison summarized in the primary result.

The primary comparison focuses on a composite outcome through study day 49. A participant is counted if either component occurs in the specified period. This makes the question broader than whether candidiasis alone occurred, and it means that the primary result cannot by itself identify the separate contribution of death and candidiasis. A later candidiasis outcome and a neurodevelopmental outcome are also posted, but they address different timeframes and questions.

3. Trial Design

This was a Phase 3 randomized trial with a parallel-group design. The registry lists quadruple masking and an enrollment of 362. The brief summary states that neonates with birthweight less than 750 grams were randomized at 33 US centers to fluconazole or placebo. The record marks the trial as completed. Its recorded start was 2008-11 and its primary completion was 2011-12.

The fluconazole regimen was 6 mg/kg intravenously or orally twice weekly for 6 weeks; placebo followed the same stated routes and schedule. The primary endpoint was assessed through study day 49. The record also lists neurodevelopmental impairment and several neonatal clinical outcomes as secondary outcomes. The posted neurodevelopmental endpoint uses a timeframe of 18-22 months corrected gestational age. Other secondary outcomes are recorded through hospital discharge, up to 15 ½ months, or through the timeframe specified for the outcome.

The primary outcome population is described as modified intent-to-treat, restricted to participants who received at least one dose of study drug. The outcome groups contain 188 participants assigned to fluconazole and 173 assigned to placebo. The posted outcome denominators need not be treated as a complete account of every randomized participant: the registry does not explain the difference between the enrollment figure and these group denominators.

Although the registry records a randomized, masked, parallel comparison, it does not report the planned allocation ratio, detailed sequence-generation or concealment procedures, or how masking was maintained. The original sample-size justification and the trial's own statistical analysis plan are not reported in the registry record. The brief summary says the research proposed a pivotal trial with 2-year neurodevelopmental follow-up, while the posted neurodevelopmental outcome timeframe is 18-22 months corrected gestational age. Details reconciling those descriptions 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.

Main Study

Reasons for not completing this period:

Long Term Follow up

Analysis population for the primary outcome, as defined in the registry: Modified intent-to-treat; only subjects who received at least one dose of study drug.

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: Infants who received at least 1 dose of study drug (Modified Intent-to-Treat population)

6. Primary Endpoint

The registry lists the primary outcome as Death or Candidiasis, measured over study day 49.

The primary endpoint is the number of participants who experienced death or candidiasis before study day 49. Death is defined as death before that day. Candidiasis includes definite cases, based on isolation of Candida from a normally sterile body fluid, and probable cases meeting the registry's stated criteria. Those criteria include more than 5 days of consecutive antifungal therapy together with thrombocytopenia below 150,000/mm3 and a positive Candida culture from a nonsterile site.

This is a composite endpoint: a participant can meet it through either component. The stated purpose of including death alongside candidiasis is reflected in the brief summary, which describes mortality as part of the primary efficacy question. Combining outcomes can make the primary question clinically broader than infection alone, but the resulting count does not show how many participants met each component separately. Component-specific primary counts are not reported in the registry record.

The reported primary endpoint is a count of participants with an event in each group, rather than a time-to-event measure. Its timeframe is fixed at study day 49, and its population is modified intent-to-treat, including only participants who received at least one dose. The posted arm counts are 31 of 188 for fluconazole and 37 of 173 for placebo. Those counts describe the composite outcome in the recorded population; they do not separately quantify the effects on death and candidiasis or establish why an event occurred.

7. Results Posted in the Registry

• Fluconazole: 16.5% (31/188) versus 21.4% (37/173) on control; risk difference -4.9 percentage points (95% CI -13.0 to 3.2), risk ratio 0.77 (0.50–1.19); unadjusted two-proportion z-test p = 0.234.

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.

Neurodevelopmental Impairment

• 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:
  • Fluconazole: 31.0% (27/87) versus 27.4% (23/84) on control; risk difference 3.7 percentage points (95% CI -10.0 to 17.3), risk ratio 1.13 (0.71–1.81); unadjusted two-proportion z-test p = 0.600.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fluconazole and the control. The interval gives the range of effects that remain compatible with the data.

Candidiasis

• 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:
  • Fluconazole: 4.3% (8/188) versus 11.0% (19/173) on control; risk difference -6.7 percentage points (95% CI -12.2 to -1.2), risk ratio 0.39 (0.17–0.86); unadjusted two-proportion z-test p = 0.015.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Fluconazole than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Stage II or Higher Necrotizing Enterocolitis

• 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:
  • Fluconazole: 13.3% (25/188) versus 13.3% (23/173) on control; risk difference 0.0 percentage points (95% CI -7.0 to 7.0), risk ratio 1.00 (0.59–1.69); unadjusted two-proportion z-test p = 0.999.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fluconazole and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes cover neurodevelopmental impairment, candidiasis, and several neonatal complications. Their timeframes and analysis populations differ, so they do not all represent the same question as the primary composite through study day 49. The overall pattern is mixed: the posted candidiasis comparison has fewer recorded cases in the fluconazole group, while the neurodevelopmental impairment comparison and the necrotizing enterocolitis comparison do not show a clear between-group separation in their posted estimates. Other secondary outcomes are listed in the registry, but only some have outcome results and comparisons described in the record.

These findings relate to the primary result as additional, distinct outcomes rather than as confirmation of the primary composite. The primary endpoint includes death or candidiasis before study day 49. The secondary candidiasis outcome covers the period before hospital discharge, up to 15 ½ months, and does not include death as part of its stated outcome. Neurodevelopmental impairment is assessed at 18-22 months corrected gestational age. Differences in definition and follow-up period mean that the secondary results should not be treated as interchangeable measures of the primary question.

The registry lists 11 secondary outcomes, but the record does not report a complete analysis set for all of them. The comparisons that are posted are unadjusted, and the record does not describe a multiplicity correction, a prespecified hierarchy, or a strategy for selecting confirmatory outcomes. General statistical explanation: when many outcomes are examined, some apparently notable results may arise by chance even if there are no true differences. This is why unadjusted secondary results generally carry less weight than a prespecified primary result, especially when the analysis plan and multiplicity handling are unavailable.

The secondary findings can help describe the range of measured outcomes and point to questions that might warrant further evaluation, but they should not override the uncertainty in the primary estimate. Nor can the available secondary outcomes establish an overall benefit or harm across all domains. The record does not report enough detail about missing follow-up, outcome ascertainment, or analysis planning to resolve those questions.

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

• Neurodevelopmental Impairment
• Candidiasis
• Stage II or Higher Necrotizing Enterocolitis
• Focal Intestinal Perforation
• Chronic Lung Disease
• Patent Ductus Arterious Requiring Surgical Ligation
• Periventricular Leukomalacia
• Retinopathy of Prematurity Requiring Laser Surgery

9. Statistical Interpretation

10. Statistical Methods Explained

The posted primary comparison is a comparison of event counts in two randomized groups. The main contrast is expressed as a risk difference: the event proportion in the fluconazole group minus the event proportion in the placebo group. A negative risk difference means the observed event proportion was lower in the fluconazole group; it does not, by itself, establish that the groups differ beyond what could occur from sampling variation. The posted estimate is -0.049.

What the confidence interval conveys

General statistical explanation: a confidence interval describes a range of values that are reasonably compatible with the observed data under the method used to calculate it. It communicates uncertainty around an estimate, rather than giving a range in which the true value is guaranteed to lie. For the primary risk difference, the recorded interval includes no difference and values on both sides. That pattern is consistent with uncertainty about the direction and size of the underlying difference. The interval is not evidence that the groups are equivalent; an equivalence conclusion would require a specified equivalence margin and an appropriate analysis, neither of which is reported in the registry record.

How to read the p-value

The unadjusted p-value for the primary comparison is 0.234. General statistical explanation: a p-value measures how unusual data at least as incompatible with a stated null hypothesis would be, if that hypothesis and the model assumptions were true. It is not the probability that the null hypothesis is true, and it does not measure the probability that chance alone caused the result. It also does not express the magnitude or clinical importance of the observed difference. The record does not report whether a particular testing hierarchy or a prespecified significance threshold governed the primary analysis.

Risk differences and relative measures

A risk difference is an absolute contrast in event proportions. The registry also posts relative measures for the primary comparison, including a risk ratio of 0.771 and an odds ratio of 0.726. These describe the comparison on different scales and should not be treated as interchangeable. General statistical explanation: a risk ratio compares the proportions directly, whereas an odds ratio compares event odds. The numerical interpretation of a relative measure depends on the scale, and a relative measure does not replace the absolute event counts. The registry does not report an adjusted model or an explanation of which measure was designated as the principal inferential contrast beyond the posted outcome comparison.

Why the endpoint definition matters

The outcome is binary for each participant: the participant either met the composite endpoint by study day 49 or did not. The composite includes death and definite or probable candidiasis. The rule for probable candidiasis combines treatment duration, thrombocytopenia, and a positive culture from a nonsterile site. Definitions influence which observations count as events; the registry gives the criteria but does not report adjudication procedures or component-specific primary results. General statistical explanation: a composite can collect several related events into one endpoint, but the combined result can conceal differences among its components.

Population and analysis details

The primary population is modified intent-to-treat and includes participants who received at least one dose of study drug. This should be distinguished from a full intention-to-treat analysis that retains every randomized participant in the group to which they were assigned, regardless of treatment receipt. The registry record does not report a separate full intention-to-treat result, per-protocol result, or detailed handling of missing outcome data. It lists no reported analyses for the secondary outcomes. Details of the statistical tests, covariate adjustment, model assumptions, prespecified analysis hierarchy, and interim analyses are not reported in the registry record.

General statistical explanation: randomization supports a fair comparison by making the treatment groups comparable in expectation, but it does not ensure that every realized sample is balanced on all prognostic factors. Masking can reduce some risks of differential care or outcome assessment, but the record's masking label does not describe implementation. Neither design feature replaces transparent reporting of analysis populations, missing-data handling, and prespecified methods. Those details are not reported in the registry record.

The posted primary analysis should therefore be interpreted as the unadjusted comparison reflected in the record, with the stated group counts, risk difference, confidence interval, and p-value. No recalculated alternative is needed to describe that result. The record does not identify a sponsor analysis that differs from it, and does not report enough detail to reconstruct a richer adjusted or protocol-based analysis.

11. Confidence Intervals and Precision

The primary estimate is a risk difference of -0.049. Its confidence interval extends across no difference and includes values below and above that point estimate. This means the posted data are compatible with a range of underlying effects, including effects in opposite directions. The interval is therefore important alongside the point estimate: the point estimate alone would understate uncertainty.

The primary group counts are 31 events among 188 participants receiving fluconazole and 37 among 173 receiving placebo. These denominators describe the modified intent-to-treat population recorded for this outcome. The registry does not report component-specific confidence intervals or separate primary estimates for death and candidiasis. It also does not report a precision target or the original sample-size justification, so the observed interval cannot be judged against a recorded design goal.

General statistical explanation: precision is influenced by the amount of information in the data and by how frequently the event occurs. A confidence interval that spans a wide range of plausible effects leaves more uncertainty than a narrower interval. In this trial, the primary comparison does not exclude no difference, and its uncertainty does not support a definitive claim about the direction of the underlying difference. Failure to establish a difference is not the same as demonstrating equivalence.

The reported unadjusted p-value of 0.234 is consistent with this uncertainty, but the p-value and interval answer different questions. The interval expresses plausible effect sizes under the calculation method, while the p-value assesses compatibility with a null hypothesis. The registry does not report whether the interval calculation was adjusted for any covariates or multiplicity. Interpretation should therefore remain tied to the posted unadjusted result rather than to unreported 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 assumptions. For binary outcomes such as the posted participant event counts, the figures are participants per arm, not total events. The calculations assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect. The original sample-size justification and assumptions are not reported in the registry record.

The 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding per-arm number for a design with a 90% chance. These are prospective planning concepts: they describe a design aimed at a stated effect, not the chance that the completed trial's result is true or the chance that the completed study detected an effect.

For the primary endpoint, the posted planning scenarios use 100%, 75%, and 50% of the observed effect. The corresponding figures rise as the assumed effect becomes smaller. For example, planning for 100% of the observed effect gives 1,004 participants per arm for 80% power and 1,343 for 90% power; planning for 50% gives 4,213 and 5,639, respectively. Smaller effects require more participants because they are harder to distinguish from random variation under the same assumptions.

These planning illustrations are not observed power. Observed power is not a useful substitute for interpreting the estimate and its confidence interval after the trial. The trial's actual design rationale cannot be inferred from these illustrations, and the registry record does not report whether its original planning used these assumptions.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.214; treatment proportion p₁ = 0.165; average p̄ = 0.189.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5541 = 1.0860.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5530 = 0.4654.
4. n = (1.0860 + 0.4654)² / (-0.0490)² = 1,003.4, rounded up to 1,004 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 <- 0.213872832369942                          # control proportion
p1 <- 0.164893617021277                          # 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(734539)
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 = 1,004 (80% power), 1,343 (90% power)
 75% of observed effect: n per arm = 1,829 (80% power), 2,448 (90% power)
 50% of observed effect: n per arm = 4,213 (80% power), 5,639 (90% power)
power.prop.test: 1003.4 
Simulated power at n = 1,004 per arm: 0.802 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists 11 secondary outcomes. It does not report a multiplicity strategy, such as adjustment of significance thresholds, a gatekeeping sequence, or a hierarchy for interpreting the secondary findings. The posted secondary comparisons include unadjusted p-values. Without a stated plan for handling multiple comparisons, those p-values should be treated as exploratory rather than as a set of independent confirmatory tests. General statistical explanation: testing many outcomes increases the chance that at least one will appear unusual by chance, so interpretation depends on how outcomes were selected and whether multiplicity was addressed.

The primary population is modified intent-to-treat and includes only participants who received at least one dose of study drug. The registry does not report a corresponding full intention-to-treat analysis or a per-protocol analysis. It also does not describe exclusions after randomization, the number of participants with unavailable outcome data, or the methods used to handle missing outcomes. The difference between the enrollment figure of 362 and the primary outcome group denominators is not explained in the registry record and should not be assigned a cause from the available information.

For the neurodevelopmental outcome, the posted denominators are smaller than those reported for the primary outcome. The registry does not explain the reasons for those denominators or report whether missing follow-up was balanced between groups. Because this endpoint is assessed at 18-22 months corrected gestational age, incomplete follow-up could affect interpretation; the extent and handling of any such missingness are not reported in the registry record.

The registry does not report the original statistical analysis plan, detailed missing-data assumptions, interim analyses, or whether any outcome definitions or analysis populations changed during the study. These omissions do not establish that such procedures were absent; they mean that the record does not document them. Consequently, the posted results can be described as recorded, but their relationship to a prespecified testing strategy and the robustness of the findings to missing-data choices cannot be assessed from the registry information.

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: necrotising enterocolitis neonatal (16.2%), sepsis neonatal (6.9%), intestinal perforation (6.4%), neonatal respiratory failure (4.8%), staphylococcal sepsis (2.1%).

The serious adverse event summary records 83 affected participants among 188 at risk in the fluconazole group and 68 among 173 at risk in the placebo group. These are participant counts for the serious adverse event summary, not counts of all individual serious events. The registry also records 1 participant with other adverse events in each group, with 188 and 173 participants at risk, respectively.

The listed serious adverse event terms include necrotising enterocolitis neonatal at 16.2%, sepsis neonatal at 6.9%, intestinal perforation at 6.4%, neonatal respiratory failure at 4.8%, staphylococcal sepsis at 2.1%, and intraventricular haemorrhage neonatal at 1.7%. These are the leading terms listed in the record, not a complete description of every event or a comparison adjusted for exposure or baseline risk.

These figures describe events recorded in the adverse-event summary. They do not establish that an event was caused by study treatment, and the registry does not report a comparative statistical analysis for these adverse-event counts. Death counts in this adverse-event summary are not reported in the registry record. The safety figures should be read separately from the primary efficacy endpoint and with the record's limitations in mind.

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

The primary result describes a randomized comparison of fluconazole and placebo for the composite of death or candidiasis by study day 49 in participants who received at least one dose. The observed count was 31 of 188 in the fluconazole group and 37 of 173 in the placebo group. The estimated risk difference was -0.049, and its confidence interval included no difference. The result therefore leaves uncertainty about the true size and direction of the difference.

It does not establish that the groups are equivalent, and it does not establish that there is no effect. A non-definitive comparison can reflect uncertainty in the estimate rather than proof of identical outcomes. Conversely, a point estimate in one direction is not sufficient to establish a treatment effect when the interval includes no difference and the unadjusted p-value is 0.234. The posted result should be understood as an estimate with uncertainty, not as a binary verdict.

The composite result does not reveal whether the observed pattern was driven by death, candidiasis, or both, because component-specific primary counts are not reported. The longer-term candidiasis and neurodevelopmental results concern distinct outcomes and timeframes. They cannot be combined informally to make a single overall conclusion, particularly because the record does not state how multiplicity was handled or provide a complete analysis plan.

The record also does not provide the original sample-size rationale, missing-data methods, or detailed analysis procedures. Those gaps constrain conclusions about whether the trial was designed to detect a particular effect and how robust the posted findings are to alternative assumptions. The secondary results and adverse-event counts add descriptive context, but the registry does not report comparative safety analyses or causality assessments.

Accordingly, the result answers a limited statistical question in the recorded population and timeframe. It does not establish a conclusion for all premature neonates, for other dosing schedules, or for outcomes beyond those reported. It is not a treatment recommendation. The distinction between an uncertain estimate and proof of no difference is central to interpreting the result.

17. Why This Trial Matters Statistically

This trial is statistically notable for asking a focused randomized question in a narrowly defined neonatal population while using a clinically broad primary composite. The trial compared fluconazole with placebo, and its primary outcome combined death and candidiasis by study day 49. A composite can make an endpoint responsive to more than one important event, but interpretation depends on knowing which components contributed to the result. The registry does not report component-specific primary counts.

The posted estimate illustrates why effect size and uncertainty should be read together. The risk difference is -0.049, but its confidence interval includes no difference and effects in both directions. The p-value is 0.234. A point estimate that favors one group is not, by itself, decisive evidence; equally, an inconclusive result is not proof of equivalence. The confidence interval shows the range of uncertainty more directly than a yes-or-no reading of the p-value.

The study also raises familiar design and reporting questions that matter in neonatal research: how the analysis population relates to randomization, how longer-term follow-up is handled, and how multiple secondary outcomes are interpreted. The registry identifies a modified intent-to-treat population and lists many secondary outcomes, but does not report missing-data methods or a multiplicity plan. Those details are important when judging both the primary estimate and exploratory findings.

Finally, the planning illustrations make clear that design requirements depend on the effect a future study aims to detect. The original design assumptions are not reported, and the illustrations based on the observed effect cannot reconstruct them. Separating retrospective estimates from prospective planning is essential: planning numbers describe a possible design, not evidence that the completed trial had a particular level of power.

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 registry record leaves important details unavailable for interpreting the trial. It does not report the original sample-size justification, the prespecified statistical analysis plan, interim analyses, allocation concealment procedures, or a detailed account of how quadruple masking was maintained. The record also does not explain the difference between enrollment of 362 and the primary outcome denominators of 188 and 173. No cause for that difference can be inferred from the posted information.

The primary analysis population is modified intent-to-treat and includes participants who received at least one dose. A full intention-to-treat result is not reported. The registry does not describe missing outcome data, exclusions after randomization, or imputation or sensitivity analyses. These omissions matter for both the day-49 outcome and longer-term follow-up.

The primary endpoint combines death and candidiasis, but the component counts are not posted. The registry defines definite and probable candidiasis but does not report how outcomes were adjudicated or whether assessors remained masked. This limits evaluation of endpoint classification and of which component contributed to the composite comparison.

The secondary outcomes are numerous, and the registry does not report a multiplicity strategy. It also does not report analyses for all listed outcomes. The neurodevelopmental outcome has a smaller posted analysis population than the primary endpoint, but the record does not explain the reasons or the extent of missing follow-up. Finally, serious adverse event counts are descriptive in the record; comparative tests, exposure-adjusted rates, and causality assessments are not reported. These limitations narrow what can be concluded from the registry results.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight — NCT00734539.
• Registry record last updated 2019-03-01; status last verified 2019-02.
• Results first posted 2014-07-17.
• 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 describes a completed Phase 3 randomized, quadruple-masked, parallel trial of fluconazole versus placebo in neonates with birthweight less than 750 grams. Enrollment was 362, and the brief summary states that participants were randomized at 33 US centers. Fluconazole was given at 6 mg/kg intravenously or orally twice weekly for 6 weeks; placebo followed the same schedule.

The primary endpoint was death or candidiasis before study day 49 in a modified intent-to-treat population restricted to participants who received at least one dose. The posted counts were 31 of 188 for fluconazole and 37 of 173 for placebo. The risk difference was -0.049, with an unadjusted p-value of 0.234 and a confidence interval that includes no difference.

The registry also lists secondary outcomes, adverse-event counts, and planning illustrations based on the observed effect. The original design assumptions, detailed analysis plan, missing-data methods, and multiplicity strategy are not reported in the registry record.