Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates (NCT00031460), a randomized phase 3 study. The primary outcome is Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment (Motor Scores)..

2. Clinical Question

The trial addressed whether suppressive oral acyclovir after neonatal herpes infection involving the central nervous system was associated with a different neurologic outcome than placebo. Both groups first received intravenous acyclovir in hospital; the randomized comparison concerned the subsequent oral treatment period. The registry describes infants with central nervous system disease that had or had not spread to other parts of the body, and separately describes those with infection involving both the skin and central nervous system. It does not report the number assigned to each disease category or provide treatment-effect estimates within those categories.

The primary outcome focused on neurologic impairment at 12 months, using motor scores from a Bayley assessment. The record also lists outcomes concerning cutaneous recurrence and detection of viral DNA in cerebrospinal fluid. The registry record does not report numerical results for the primary comparison, so the direction, size, and precision of any treatment-group difference cannot be described from this record.

3. Trial Design

This was a phase III, randomized, triple-masked, parallel-group trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The registry lists enrollment of 46 participants and a completed status. The recorded start was 1997-12, and primary completion was 2008-02.

All participants were described as receiving 21 days of intravenous acyclovir in hospital. They were then randomly assigned to oral acyclovir or placebo for 6 months. The registry description distinguishes participants according to the extent and location of infection, including central nervous system disease with or without spread and disease involving the skin and central nervous system. The precise allocation procedure within these categories is not reported in the registry record.

Triple masking indicates that the record classifies the trial as masked at three levels, but it does not identify the people covered by masking. Further details of the masking procedures, allocation concealment, treatment adherence, and handling of treatment changes are not reported in the registry record.

The registry states that infants in the US and Canada would participate for 5 years, with physical, hearing, eye, and nervous-system examinations throughout the study. This follow-up description does not change the stated primary endpoint time: the primary neurologic outcome was assessed at 12 months of life. The record does not explain how the longer follow-up measures related to the primary analysis. It also does not report the protocol’s sample-size justification, planned interim analyses, or a detailed statistical analysis plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Subjects enrolled while on 2 - 3 weeks of IV acyclovir therapy who have positive cerebrospinal Fluid (CSF) herpes simplex virus (HSV) PCR results within 48 hours prior to IV therapy completion, are not randomized.

Overall Study

Reasons for not completing this period:

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 Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment (Motor Scores)., measured over At 12 months of life..

The primary endpoint is the number of participants with neurologic impairment at 12 months of life, measured using motor scores from a Bayley neuro-developmental assessment. The description specifies that the scores are for participants who completed 6 months of blinded therapy. It classifies scores of at least 115 as suggesting accelerated performance, scores from 85 to 114 as within normal limits, scores from 70 to 84 as mildly delayed, and scores of 69 or lower as significantly delayed.

Motor development is relevant to the trial’s question because the study evaluated outcomes after neonatal herpes simplex virus infection involving the central nervous system. A standardized developmental assessment can translate performance into a defined outcome rather than relying only on an unstructured clinical impression. However, the registry record does not specify which of the listed score categories counted as “neurologic impairment” for the primary endpoint. That operational definition matters: different choices about the categories included would change which participants meet the endpoint.

The record gives the measurement time and score classifications, but it does not report the number meeting the primary endpoint in either treatment group, an estimated between-group effect, or a confidence interval. It therefore does not allow a reader to assess the observed frequency of impairment or the precision of a treatment comparison. The endpoint’s listed population is also limited to participants completing blinded therapy; the registry record does not explain how participants who did not complete therapy were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization is intended to create treatment groups that are comparable, on average, with respect to factors that could influence outcomes. It supports a fair comparison of assigned treatments, but it does not guarantee identical groups, particularly in a trial with limited enrollment. The record identifies random assignment and a parallel-group design, but it does not describe the random sequence, concealment procedures, or whether assignment was stratified by disease presentation.

What does masking contribute?

Masking is intended to reduce the chance that knowledge of treatment assignment changes care, outcome assessment, or reporting. The record classifies the trial as triple-masked. It does not identify which roles were masked, whether the placebo matched the active treatment in appearance and administration, or whether masking was assessed. Those details are not reported in the registry record, so the label alone cannot establish how masking worked in practice.

How should a participant-count endpoint be compared?

The primary outcome is expressed as the number of participants meeting a defined condition. For a treatment comparison, an analysis would generally need to show the number meeting the endpoint and the relevant denominator in each group, then estimate the difference or another prespecified contrast. A confidence interval would convey the range of effects reasonably compatible with the data under the model used. A narrower interval indicates greater precision; a wider interval indicates more uncertainty. These are general statistical principles. The registry record does not report the counts, contrast, confidence interval, or test for this primary outcome.

The endpoint is described as binary at the participant level, but its classification depends on which Bayley motor-score categories count as impairment. The registry lists score ranges and descriptions, yet does not state which ranges were combined for the primary analysis. Without that definition, readers cannot reconstruct the endpoint from score-level data or know whether the intended comparison treated categories separately or combined them.

Why are denominators and missing outcomes important?

A count has meaning only alongside the population from which it was counted. For example, an outcome count among participants completing blinded therapy answers a different question from a count among everyone randomized if some participants do not complete treatment or assessment. The registry outcome description refers to completers, but does not report the analysis population, the number assessed in each group, or the handling of missing 12-month assessments. The method for addressing missing data is not reported in the registry record.

Missingness can affect interpretation when the availability of an assessment is related to health status, treatment assignment, or other factors associated with the outcome. General approaches include analyses restricted to observed outcomes, imputation under stated assumptions, and sensitivity analyses that examine how conclusions change under alternative assumptions. These approaches are not interchangeable. The registry record does not identify which approach, if any, was planned or used.

What does the analysis record contain?

No analysis entries are listed in the registry record. Thus, the record does not identify a statistical model, adjustment variables, a method for estimating treatment effects, a significance test, or a confidence-interval procedure for the primary comparison. It also does not report whether analyses followed randomized assignment or another analysis population. These omissions do not establish that no analysis was performed; they mean that its details are not reported in the registry record.

The record identifies four outcome measures overall and names secondary outcomes involving cutaneous recurrence and detection of herpes simplex virus DNA in cerebrospinal fluid. Multiple outcomes can create multiplicity: the more comparisons considered, the greater the chance that at least one result appears unusual by chance if each is interpreted without accounting for the family of tests. General methods for addressing this include identifying a primary outcome in advance, specifying a testing hierarchy, or adjusting inference across comparisons. The registry record does not report a multiplicity strategy or the analysis details for the secondary outcomes.

How should planning illustrations be read?

The stated planning illustration assumptions use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial’s original sample-size justification. A sample-size calculation asks how many participants would be needed under chosen assumptions to detect a target effect with a chosen operating characteristic. It does not estimate the probability that the observed result is true, and it is not observed power. The record does not report the protocol’s design assumptions or sample-size justification.

For a binary outcome, planning calculations depend on assumptions about event frequencies and the effect size to detect. If an observed effect is used as the reference, planning for a fraction of that effect explores sensitivity to a smaller target. These calculations can help illustrate how design requirements change with assumptions, but they do not supply missing trial results. In this record, the primary outcome lacks a reported treatment comparison, so the observed result and its precision cannot be evaluated from the registry entry.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary neurologic outcome and secondary outcomes concerning cutaneous recurrences and herpes simplex virus DNA detection in cerebrospinal fluid. It also lists four outcome measures overall. When several outcomes or comparisons are examined, multiplicity matters because repeated testing can increase the chance of at least one apparently notable result arising by chance. General approaches include prespecifying a primary outcome, using a hierarchy for secondary questions, or adjusting the interpretation of multiple tests. The registry record does not report a multiplicity procedure, a testing hierarchy, or analysis details for the secondary outcomes.

Missing-data methods are also not reported in the registry record. The primary outcome description refers to participants completing 6 months of blinded therapy, but the record does not give the number who completed therapy or the number with an assessment at 12 months in either arm. It does not describe withdrawals, reasons for missing assessments, imputation, or sensitivity analyses.

The analysis population is not reported in the registry record. It is therefore unclear whether the primary comparison was intended to include all randomized participants, only those completing treatment, or another defined group. These choices affect the question answered by an analysis and can affect its validity. The registry record also lists no analysis entries, leaving the model and handling of participants with incomplete outcome information unspecified.

11. 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: herpes simplex virus (38.1%), neutropenia (37.5%), seizures (14.3%), gastroesophageal reflux (8.3%), otitis media (8.3%).

The registry reports serious adverse-event figures for both arms. In the acyclovir group, 24 participants were at risk and 17 were affected; in the placebo group, 21 were at risk and 15 were affected. The record also reports other adverse-event figures: 24 participants at risk and 18 affected in the acyclovir group, and 21 at risk and 13 affected in the placebo group. These are counts, not treatment-effect estimates, and the registry record does not provide a statistical comparison for them.

The listed serious-event terms are herpes simplex virus at 38.1%, neutropenia at 37.5%, seizures at 14.3%, gastroesophageal reflux at 8.3%, otitis media at 8.3%, and bradycardia at 4.8%. The registry record does not identify these percentages by treatment arm or give the denominators and event-level details needed to interpret them fully. It also does not report deaths in the arm-level safety information.

Adverse-event counts describe events recorded under the registry’s reporting approach; they do not, by themselves, show that a treatment caused an event. Interpretation would require context such as timing, severity, attribution, exposure, and completeness of follow-up, which is not reported in the registry record.

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

The registry record describes a randomized comparison of oral acyclovir and placebo after an initial course of intravenous acyclovir in infants with herpes simplex virus infection involving the central nervous system. It specifies the primary outcome, the assessment time, and the broad score classifications used by the developmental assessment. It also records enrollment and selected safety counts.

It does not report the primary outcome counts by arm, a treatment-effect estimate, a confidence interval, or a statistical test. It therefore cannot establish from the registry record whether the groups differed in neurologic impairment at 12 months, how large any difference was, or how precisely it was estimated. The missing operational definition of impairment further limits interpretation of the endpoint as registered.

The record’s completion status does not supply the absent outcome results. Likewise, a planning illustration based on an observed effect is not a report of trial efficacy, nor is it evidence of observed power. Sample-size planning depends on assumptions and cannot replace a treatment estimate with uncertainty information.

The serious adverse-event counts and listed event terms provide a limited description of safety reporting. They do not on their own establish a causal relationship or a comparative safety conclusion. More detailed information about event timing, severity, attribution, and analysis is not reported in the registry record.

Accordingly, the registry entry is informative about the study question and broad design, but insufficient for judging the magnitude or precision of the primary treatment comparison. A complete statistical interpretation would require the outcome results and analysis details that are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial’s statistical question is important because it separates the initial treatment common to both groups from the randomized comparison that followed. Both groups received intravenous acyclovir in hospital; randomization concerned the subsequent 6 months of oral acyclovir or placebo. Keeping that distinction clear is essential when interpreting what a treatment contrast is intended to estimate.

The primary endpoint also illustrates why outcome definitions matter. A Bayley motor assessment produces a score, while the registered primary outcome is a count of participants with neurologic impairment. The registry lists several score categories but does not say which categories constitute impairment. A clear threshold or category-combination rule is necessary for readers to understand, reproduce, and interpret a binary outcome.

Precision is as important as the direction of an estimate. A treatment comparison is most informative when it includes group denominators, the estimated effect, and an interval describing uncertainty. The registry record does not report these for the primary outcome, so neither the magnitude nor precision of the comparison can be evaluated from this entry.

Finally, the record distinguishes an outcome question from a planning calculation. Sample-size illustrations based on an observed effect can explore hypothetical design assumptions, but they do not serve as trial results or as a substitute for the original design rationale. Taken together, the entry shows why transparent outcome definitions, analysis populations, missing-data methods, and treatment-effect estimates are central to assessing a clinical trial.

14. 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 does not report numerical results for the primary neurologic outcome or the listed secondary outcomes. It provides no treatment-effect estimate, confidence interval, or statistical test for the primary comparison. This prevents assessment of the direction, magnitude, and precision of the randomized contrast.

The definition of primary neurologic impairment is incomplete in the record. It gives motor-score categories but does not state which categories were counted as impairment. The outcome description refers to participants completing blinded therapy, but the record does not report the number completing therapy, the number assessed at 12 months, or the analysis population.

Methods that could materially affect interpretation are not reported in the registry record. These include the allocation procedure, the identities of masked roles, the statistical model, missing-data handling, and any multiplicity strategy. The record also does not provide the original sample-size justification or interim-analysis plan.

The safety information is limited to arm-level counts and a list of serious-event terms with percentages. The record does not report event timing, severity details, attribution, or enough information to interpret those percentages by treatment arm. These limitations are specific to the information recorded for this trial and should not be filled in by assumption.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates — NCT00031460.
• Registry record last updated 2012-05-16; status last verified 2009-10.
• Results first posted 2010-04-09.
• 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.

18. Record Summary

NCT00031460 is a completed, randomized, triple-masked, parallel-group phase III trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It enrolled 46 participants. The recorded start was 1997-12, and primary completion was 2008-02.

Participants received 21 days of intravenous acyclovir in hospital, followed by random assignment to 6 months of oral acyclovir or placebo. The primary outcome was participants with neurologic impairment at 12 months, measured using Bayley motor scores. Secondary outcomes concerned cutaneous recurrence and herpes simplex virus DNA detection in cerebrospinal fluid.

The registry record does not report numerical results for the primary or secondary outcomes, the primary analysis, or the analysis population. It lists serious adverse-event counts and selected event terms, but provides limited context for interpreting them.