Prospective Research in Infants With Mild Encephalopathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Prospective Research in Infants With Mild Encephalopathy (NCT01747863), a registered phase not stated study. The primary outcome is Percentage of Infants With Evidence of Neurological Dysfunction, Brain Injury and/or Abnormality..

2. Clinical Question

The study was designed to describe the natural history of infants who were not eligible for therapeutic hypothermia, rather than to estimate a treatment effect. Its primary question combines findings from different kinds of assessment: brain imaging, electrical brain activity, and clinical neurological examination. The registry also describes follow-up at 18-22 months of age and secondary outcomes including seizures, hospital stay, feeding support at discharge, death, and long-term outcome.

That scope matters when interpreting the question. A composite outcome can count an infant as having an abnormal result if any qualifying component is present. It therefore asks whether evidence of dysfunction or injury appeared on at least one of the specified assessments, not whether every assessment was abnormal or whether a particular component was more common. The registry record does not report the observed primary outcome result or a comparison with infants who received therapeutic hypothermia.

3. Trial Design

PRIME was a multicenter observational pilot study sponsored by McGill University Health Centre/Research Institute of the McGill University Health Centre. The registry lists the study as completed, with enrollment of 63. The recorded start is 2012-12 and primary completion is 2015-12.

Eligible participants were described as infants with evidence of a perinatal event and neonatal encephalopathy who did not qualify for therapeutic hypothermia. The brief description centers on early diagnosis of mild neonatal encephalopathy, at or before 6 hrs of age. The registry lists a single Mild NE group. It does not describe randomization, an allocation method, or a comparator group; the allocation field is not stated. The listed group is therefore not a like-for-like control comparison.

The assessment plan described in the study summary includes neurologic examinations using a modified Sarnat score at early assessment, 24 hrs, and before discharge; aEEG at 6 ± 3 hrs of age; brain MRI before discharge home to 30 days of age; and follow-up at 18-22 months of age. These are observational assessments, not assignments to different treatments. The registry’s intervention listing names neurologic examination, while the study summary describes the broader assessment schedule.

The primary outcome is framed as the percentage of infants with evidence of neurological dysfunction, brain injury, or abnormality. Secondary outcomes include seizures, length of hospital stay, feeding support at discharge, mortality, and longer-term outcome. A sample-size justification, eligibility details beyond the summary, and a full statistical analysis plan are not reported in the registry record. The registry also does not report an analysis population or the number of participants contributing data to each outcome.

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

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 Percentage of Infants With Evidence of Neurological Dysfunction, Brain Injury and/or Abnormality., measured over 1 month.

The primary endpoint counts participants with evidence of neurological dysfunction, brain injury, or abnormality, with a stated timeframe of 1 month. The registry defines a qualifying result as any one of the following: a brain MRI injury-pattern score using NICHD-NRN criteria greater than 0; an abnormal aEEG background pattern, including voltage or background pattern, at 6 ± 3 hrs of age; or any abnormality on the neurological examination at discharge.

This is a binary participant-level composite: a participant either meets the definition or does not, based on the available qualifying assessments. The brief summary describes the outcome as the percentage of infants with at least one abnormality. To interpret such a percentage, readers need both the number meeting the definition and the number assessed; neither is reported for the primary outcome in the registry record.

General: combining related assessments can capture evidence that appears in more than one clinical domain without requiring every test to be abnormal. The trade-off is that the composite groups together findings that may differ in type and clinical meaning. A composite result alone cannot show which component drove the overall count. Component-specific results would be needed to distinguish MRI findings from aEEG or examination findings; those primary component results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary participant outcome represent?

The primary endpoint is a count of participants meeting an event definition, with the study summary expressing the intended result as a percentage. A percentage requires a numerator—the participants meeting the composite definition—and a denominator—the participants assessed for it. The registry gives an enrollment of 63 but does not report the primary numerator or denominator. Enrollment alone should not be substituted for the number with complete endpoint assessment.

General: for a binary outcome, an estimate of the event proportion is a compact description of observed frequency. It does not describe the severity of each finding, the time course of a finding, or the probability for every future participant. The definition also matters: a composite that accepts any qualifying component will answer a different question from one requiring all components or using only a single assessment.

How should uncertainty be understood?

General: a confidence interval presents a range of values compatible with the observed data under a specified statistical procedure and its assumptions. A narrow interval indicates greater precision than a wide interval, but neither interval width nor statistical significance establishes clinical importance. For a proportion, the choice of interval method can matter, especially when event counts or denominators are limited. The registry does not report a primary estimate, interval, or method for calculating one, so no precision assessment can be made from the posted results.

The registry record does not report a statistical analysis plan, a hypothesis test, or a model for the primary endpoint. It is not possible to say whether the intended analysis was a simple proportion, an adjusted estimate, or another approach. No method should be attributed to the investigators unless it is reported in the registry record.

What does the planning illustration mean?

The planning illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of an observed effect. Those are assumptions for planning illustrations, not reported features of the PRIME design. The study is described as observational and the registry lists a Mild NE group without a comparator arm. Equal allocation between two arms therefore does not describe the listed study structure.

General: a planning sample size estimates how many participants would be needed under a chosen design, outcome, effect assumption, and error-rate convention. It is conditional on those choices and is not a forecast of what a completed study will find. It is also not observed power. A planning illustration based on an observed effect can be especially dependent on that effect estimate; uncertainty in the estimate and differences between the illustrative assumptions and the actual design limit its relevance. The registry does not report the trial’s own sample-size justification.

Could clustering or repeated assessments matter?

General: when participants are recruited at multiple centers, outcomes may be more alike within a center than across centers. If that dependence is present, a method that treats every observation as fully independent can give misleading uncertainty. Whether and how to account for center-level clustering is a protocol and analysis question; the registry record does not report such a method.

The assessment description includes examinations at different times, as well as aEEG, MRI, and later follow-up. General: repeated or differently timed measurements need clear rules for which observations count toward an endpoint and how unavailable assessments are handled. The composite definition identifies qualifying findings, but the registry does not report a detailed analysis procedure for incomplete or discordant assessment records.

Finally, the record’s outcome data should be distinguished from its design description. The registry reports 0 analyses and does not give a primary endpoint estimate, component estimates, confidence intervals, or test results. Statistical concepts can clarify what such information would mean, but they cannot recover results that are not reported.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Mild NE")
n      <- c(54)
events <- c(28)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Mild NE  54  28  51.9  37.8  65.7  38.9  64.6  38.8  64.6

11. Multiplicity, Missing Data and Analysis Populations

The registry describes a primary composite outcome and several secondary outcomes. The secondary outcomes listed include seizures, length of hospital stay, feeding support at discharge, mortality, and longer-term outcome; the study summary also describes abnormalities on MRI, aEEG, and neurological examination. The registry reports six outcome measures, but it does not provide results for these outcomes in the record.

Multiplicity arises when several outcomes or statistical tests are examined. General: as the number of tests increases, the chance of at least one apparently unusual result can increase if each test is interpreted separately. A prespecified hierarchy or an adjustment can address some multiplicity concerns, but the appropriate approach depends on the study question and analysis plan. No multiplicity strategy or testing hierarchy is reported in the registry record, and no analyses are listed.

The record does not describe missing-data counts, reasons for unavailable assessments, imputation, or sensitivity analyses. It also does not define analysis populations such as all enrolled participants versus those with an observed endpoint. General: missing outcome data can affect both the denominator and the interpretation of an estimated proportion, particularly if participants without assessments differ from those assessed. Without counts and handling rules, the extent and direction of any such effect cannot be assessed.

The enrollment count should not be treated as proof that every outcome was observed for every participant. The registry record does not report outcome-specific denominators, so neither completeness nor the influence of missing data can be quantified.

12. 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.

The adverse-event record lists the Mild NE group with 63 participants at risk, 0 participants affected by serious adverse events, and 0 affected by other adverse events. These are the figures reported in the registry record. The record’s death field is not populated with a count, so it should not be interpreted as a reported zero.

These entries describe adverse-event reporting categories and are distinct from the primary composite neurological endpoint. They should not be read as showing that no participant had a seizure, MRI abnormality, aEEG finding, examination abnormality, feeding need, or other clinical outcome. Those outcomes are listed separately, and their results are not reported in the registry record.

General: a zero event count in a registry category means no affected participants are recorded in that category for the stated risk group. It does not prove that the underlying risk is zero, and its interpretation depends on how events were defined, collected, and reported. The record does not provide further event definitions or explanatory detail for these entries. These figures alone also cannot establish comparative safety, since no comparator group is described.

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

The record establishes that PRIME was a completed multicenter observational pilot with enrollment of 63 and a defined primary composite outcome for infants with mild neonatal encephalopathy who did not qualify for therapeutic hypothermia. It also documents the intended assessment domains and lists several secondary outcomes. This information can help readers understand what the study set out to describe.

It does not establish how many participants met the primary endpoint. The registry record does not report that outcome’s numerator, denominator, percentage, or uncertainty interval. It therefore does not support a quantitative statement about the frequency of qualifying abnormalities in the cohort. The 0 adverse-event entries are not a substitute for that missing outcome information.

The observational design is important. The study was intended to describe natural history, and the registry does not describe a comparator group or random assignment. Any observed cohort outcome, if reported elsewhere, would describe the participants assessed under the study’s procedures; it would not by itself show that a treatment caused a difference. No treatment effect can be estimated from the registry information.

General: a composite outcome can be useful when different assessments capture related aspects of a research question. However, the composite alone does not show whether findings were common across components or concentrated in one component. Nor does the planned follow-up at 18-22 months establish what the longer-term findings were; the registry record does not report those results.

The most defensible interpretation is consequently limited: the record specifies a clinically oriented observational question and the criteria used to define its primary outcome, but it does not report the primary result or analyses needed to quantify it. Missing results should not be converted into a positive or negative finding.

14. Why This Trial Matters Statistically

This study illustrates a statistical challenge common to observational research: a carefully described question and endpoint do not, on their own, provide an estimate of the outcome. The PRIME registry record identifies the intended population, a multi-assessment composite, and a range of secondary outcomes. Yet without outcome counts and denominators, readers cannot assess the observed frequency or its precision.

The composite also makes endpoint construction visible. MRI, aEEG, and neurological examination can identify different forms of evidence, and the rule that any qualifying finding counts determines what the overall proportion would represent. Reporting component results alongside a composite can help readers understand whether the overall result reflects one domain or several. Those primary component results are not reported in the registry record.

The observational, single-group description also clarifies the boundary between descriptive and comparative inference. A cohort can contribute information about outcomes in the population it studies, but it does not provide a randomized estimate of what would have happened under another treatment when no comparator is described. Statistical precision cannot repair the absence of a comparison needed for a causal question.

Finally, the gap between enrollment and outcome-specific reporting matters. Readers need to know who contributed data to each endpoint and how unavailable assessments were handled to judge completeness and possible bias. Such details are not reported in the registry record. The study is therefore statistically instructive both for its explicit composite definition and for the limits imposed by absent outcome and analysis reporting.

15. 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 principal limitation for interpretation is that the registry record does not report the primary outcome result. It gives no numerator, endpoint denominator, percentage, confidence interval, or component-specific primary result. Enrollment of 63 does not reveal how many participants had the assessments needed for the composite.

The study is described as observational, and no comparator group or allocation method is reported. This limits the research question to description of outcomes in the cohort; it does not support a randomized or causal treatment comparison. The registry lists the Mild NE group, but the group is not a control arm against another group in the reported design.

The endpoint combines MRI, aEEG, and discharge neurological examination findings. Although the criteria are described, the registry does not report how often each component was observed, how discordant or unavailable assessments were handled, or whether all participants had each assessment. The study summary describes a multicenter assessment schedule and longer-term follow-up, but outcome-specific completeness and results are not reported.

Statistical methods are also insufficiently described for independent appraisal. The registry reports 0 analyses and does not provide an analysis plan, uncertainty method, multiplicity strategy, missing-data approach, or analysis-population definition. A sample-size justification for the study is not reported in the registry record. The available adverse-event entries are limited to the reported categories and do not replace the missing primary and secondary outcome results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Prospective Research in Infants With Mild Encephalopathy — NCT01747863.
• Registry record last updated 2025-01-28; status last verified 2024-12.
• Results first posted 2025-01-28.
• 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.

19. Record Summary

PRIME (NCT01747863) is a completed multicenter observational pilot sponsored by McGill University Health Centre/Research Institute of the McGill University Health Centre. The registry records enrollment of 63, a start of 2012-12, and primary completion in 2015-12.

The study concerns infants with mild neonatal encephalopathy who did not qualify for therapeutic hypothermia. Its primary outcome is a participant-level composite: any qualifying MRI, aEEG, or discharge neurological examination abnormality, with a stated timeframe of 1 month. The registry also lists seizures, hospital stay, feeding support, mortality, and longer-term outcomes.

The primary endpoint result, outcome-specific denominators, statistical analyses, and sample-size justification are not reported in the registry record. The adverse-event record lists 0 serious and 0 other adverse events among 63 participants at risk; these figures do not report the primary neurological outcome.