Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia (NCT01862250), a na phase 1, phase 2 study. The primary outcome is Steady State Clonidine Blood Levels During Hypothermia.

2. Clinical Question

The broader research question concerns the safety of clonidine while infants with hypoxic-ischemic encephalopathy undergo therapeutic hypothermia. The record describes interest in maximum tolerated dose, shivering, cardiovascular measures, core body temperature, cerebral autoregulation and the association between blood levels and changes in these measures. Those aims provide context, but they should not be mistaken for reported findings: the registered primary outcome is blood levels, and the record does not include numeric results for that outcome.

The study summary explains that clonidine was being investigated in this setting, where agitation and shivering during cooling are concerns. It also describes the investigators’ interest in short-term cardiovascular safety. These are motivations and research aims, not evidence that a particular clinical benefit or harm was demonstrated. With no comparator group, the study is best read as an early-phase investigation of observations among infants receiving clonidine, rather than as an estimate of how clonidine compares with another approach.

3. Trial Design

This is a completed Phase I-II clinical trial sponsored by Johns Hopkins University. The registry describes a single-group model, allocation as NA, and no masking. The listed enrollment is 13. The study began on 2013-10-03, reached primary completion on 2015-04-14, and is marked completed.

The group description identifies infants with hypoxic-ischemic encephalopathy who received intravenous clonidine during therapeutic hypothermia. The specified dose was 1µg/kg/dose, given either every 6 or 8 hrs from the start of cooling to the end of re-warming. The primary outcome is steady-state clonidine blood levels during hypothermia, with a timeframe of 3 days. The primary outcome description says trough levels were measured after 4-7 intravenous doses given at an interval of every 8 hrs.

This design can describe observations in the treated group, but it cannot by itself separate changes associated with clonidine from changes over time, cooling, the underlying condition, or other care. In general, a concurrent comparison group helps estimate how outcomes differ under alternative assigned conditions. No such control group is described in this registry record, and the skip note cautions that the arms are not a like-for-like control comparison.

The record lists Presence of Shivering After Clonidine and Time to Passive Rewarming as secondary outcomes. It also records 4 outcome measures, while detailed numeric results for those additional measures are not included in the registry record described for this analysis. The listed trial phase and aims indicate an early investigation focused on safety and pharmacologic observations; they do not establish that a particular dose was tolerated or that a particular effect occurred.

The registry record does not report a detailed statistical analysis plan, a sample-size justification, or an account of interim analyses. It is therefore not possible to describe those design decisions as features of the study. The information available supports describing the registered structure and the measurements, while leaving the rationale for the design and the analysis procedures uncertain.

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: Study medication was not administered for one participant

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only 8 babies were assessed for this outcome because the rest did not have a steady state trough level performed during cooling

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 Steady State Clonidine Blood Levels During Hypothermia, measured over 3 days.

The primary endpoint is titled Steady State Clonidine Blood Levels During Hypothermia. It measures trough clonidine blood levels in ng/ml. A trough measurement is taken in relation to a dosing interval, rather than being a general measure of all blood concentrations over time. The record describes measurement after 4-7 intravenous doses given every 8 hrs. It reports that the mean number of doses before levels were drawn was 5.3, with SD 0.37, and that the mean time after the last dose before measurement was 9hrs, with SD 2.7hrs.

In general, measuring drug levels can describe the concentrations observed under a particular dosing schedule and clinical setting. Such measurements may help characterize drug exposure and can be considered alongside safety observations. They do not, on their own, demonstrate clinical benefit, establish a safe dose, or show that a blood level caused a change in another measure.

The endpoint is specified as a median with full range, but the numeric median and range are not reported in the registry record. Only 8 babies were assessed for this outcome because the others did not have a steady-state trough level performed during cooling. That limitation matters when interpreting the endpoint: it describes the assessed subset, and the record does not explain whether those with measurements differed from those without them. The intended measurement is clear, but its result and its precision cannot be evaluated from the reported endpoint information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help clarify what can and cannot be learned from the reported information. The registry record identifies the endpoint and some descriptive details, but it does not report a complete analysis plan or numeric primary result. Therefore, the explanations below describe general statistical principles and do not imply that a particular unreported method was used.

What does a median with full range describe?

The primary endpoint is specified as a median with full range. In general, the median is the middle of the ordered observations and gives a measure of the center that is less affected by unusually high or low values than the arithmetic mean. The full range describes the lowest and highest observed values. Together, these summaries can convey both a typical observed concentration and the span of concentrations, though the range is sensitive to the values at the extremes and does not show the full shape of the data.

The record does not include the actual median or range for clonidine blood levels. It does report a mean number of doses before measurement of 5.3 with SD 0.37, and a mean time after the last dose before measurement of 9hrs with SD 2.7hrs. Those are descriptions of the measurement circumstances, not the primary blood-level result. The primary outcome’s stated summary type should not be confused with those means and standard deviations.

What does the endpoint timing mean?

A trough measurement is intended to characterize a concentration in relation to a dosing interval. In general, comparing trough measurements is most interpretable when the dosing and collection timing are sufficiently consistent. Here, the description says levels were drawn after 4-7 doses, with dosing every 8 hrs, and gives the mean time after the last dose before measurement. Those details help readers understand the sampling context. The record does not report individual collection times, individual concentrations, or an analysis of how timing related to concentrations.

The outcome timeframe is 3 days. That timeframe identifies the registered period associated with the endpoint; it does not supply a concentration result or establish how the level changed over time. The registry does not report serial results or a model describing the concentration course.

Why does a single group limit inference?

In general, a treatment comparison needs information about outcomes under more than one condition to estimate how outcomes differ between conditions. A single-group study can describe observations during treatment and can be useful for early safety or measurement questions. It cannot, by itself, show whether an observed outcome was caused by the treatment. In this trial, the registry lists a single-group model, allocation as NA, and no masking, with no concurrent control group described.

That matters because participants’ outcomes occur in the setting of therapeutic hypothermia and hypoxic-ischemic encephalopathy. Changes in a measured outcome may reflect multiple influences. Without a like-for-like comparison, the registry’s observations cannot isolate the contribution of clonidine from those other influences. The study summary’s aims—including shivering, cardiovascular measures, body temperature, cerebral autoregulation, and blood-level associations—remain aims unless corresponding results and analyses are reported.

How should missing measurements be understood?

Only 8 babies were assessed for the primary outcome because the others did not have a steady-state trough level performed during cooling. In general, an unavailable measurement reduces the information available for an endpoint. The implications depend in part on why it is unavailable and whether the observed participants differ systematically from those without a measurement. The registry gives the stated reason but does not report a missing-data analysis, a comparison of measured and unmeasured infants, or an analysis population definition beyond the primary-outcome description.

It is important not to assume that the primary outcome population, enrollment, and safety population are interchangeable. The registry reports enrollment of 13, primary endpoint assessment in 8 babies, and a safety at-risk count of 12. The reason for the different denominators is not reported in the registry record. No additional participant flow or explanation should be inferred from those counts alone.

What can the safety counts tell readers?

In general, an event count describes how many recorded events occurred in the stated group and population. A count of zero means no events of that category were recorded in the reported data; it does not prove that the underlying event risk is zero. Precision is especially limited when the number at risk is modest, and a single-group record cannot provide a comparative risk estimate. The registry lists zero serious events, zero other events, and zero deaths among 12 at risk. It does not report a confidence interval or a comparative safety analysis in the registry record.

How should planning illustrations be read?

Sample-size illustrations are planning calculations, not observations from the trial and not estimates of the trial’s power after the fact. The stated planning framework uses 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 fraction of the observed effect. Time-to-event illustrations are described as total event counts; other illustrations are described as participants per arm. These assumptions do not describe the enrolled single-group design and should not be read as the trial’s own design or analysis plan. The registry record does not report a sample-size justification for this study, and the planning assumptions alone do not supply missing trial results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures, names Presence of Shivering After Clonidine and Time to Passive Rewarming as secondary outcomes, and identifies steady-state clonidine blood levels during hypothermia as the primary outcome. The details available do not fully describe the remaining outcome measures or provide numeric results for the secondary outcomes. The registry records 0 analyses. This means no analysis entries are listed in the information at hand; it does not establish that no analyses were conducted.

Multiplicity arises when several outcomes or comparisons are evaluated. In general, examining many results can increase the chance that at least one appears notable by chance, so an analysis plan may specify a primary endpoint and how secondary outcomes will be interpreted. The record identifies a primary endpoint but does not report a multiplicity strategy, a hierarchy for secondary outcomes, or an adjustment procedure. It is not appropriate to assume one was or was not used in analyses outside the registry record.

For the primary endpoint, only 8 babies were assessed because the others did not have a steady-state trough level performed during cooling. The registry does not report imputation, sensitivity analyses, reasons for missing measurements beyond that description, or an assessment of whether missingness could affect interpretation. In general, missing outcome data can limit precision and may introduce bias if measurement availability is related to the outcome or participant circumstances. The available record is insufficient to determine the direction or size of any such effect.

The registry reports enrollment of 13 and a safety population of 12 at risk, in addition to the primary endpoint assessment count. It does not explain how the populations were defined or why the denominators differ. A complete intention-to-treat, per-protocol, or other analysis population is not reported in the registry record. These omissions mean the analysis populations and handling of missing information cannot be reconstructed from the reported details.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The serious adverse-event figures list 12 at risk, 0 serious events, 0 other events, and 0 deaths for the clonidine infants with hypoxic-ischemic encephalopathy group. The top serious terms list is empty. These are reported counts, not evidence that the true risk of serious or other events is zero.

In general, an observed count is interpreted in the context of how many people were monitored, for how long, and how events were defined and collected. The registry record does not give additional detail about event definitions, individual follow-up, or the completeness of ascertainment in the registry record. It also does not provide a comparison group. Therefore, the counts cannot show whether event risk differed from what would have occurred without clonidine or under another treatment.

The safety denominator of 12 is distinct from the listed enrollment of 13 and the 8 babies assessed for the primary outcome. The registry does not explain the difference. The zero counts should be read narrowly as the adverse-event data reported for the stated at-risk group, not as proof of absence of harm or as a comparative safety conclusion.

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

The record establishes that a completed Phase I-II, single-group study investigated clonidine in infants with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia. It describes intravenous dosing, the timing of trough-level measurement, and an endpoint focused on steady-state clonidine blood levels. It also reports zero serious events, zero other events, and zero deaths among 12 at risk in the listed group.

Those details do not establish a clinical benefit or a lack of clinical benefit. The registry record does not report the numeric primary blood-level result, and the registry entries do not include numeric results for shivering, time to passive rewarming, cardiovascular measures, temperature, or cerebral autoregulation. The stated research aims are not findings. Likewise, the absence of reported serious events in the listed safety group does not prove that the risk of such events is zero.

The design also limits what can be attributed to clonidine. Because the study is single-group and has no concurrent control group, it cannot directly estimate how outcomes would differ under an alternative approach. General changes during cooling and re-warming, the underlying condition, and other influences cannot be separated from treatment effects by a single-group observation alone.

Only 8 babies were assessed for the primary endpoint, while enrollment is listed as 13 and the safety count at risk is 12. The registry states why the primary trough measurement was unavailable for the others, but does not explain the distinct safety denominator or report analyses of missingness. Those differences are relevant when judging how broadly endpoint and safety observations represent the enrolled group.

The appropriate reading is therefore descriptive and cautious: the record documents a study design and selected observations, but does not give enough outcome information to characterize the measured blood levels or establish comparative effectiveness or safety. It does not resolve the broader questions posed in the study summary about potential neuroprotective properties.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a research question, an endpoint definition, and a reported result. The primary outcome is clearly identified as steady-state clonidine blood levels during hypothermia, with a specified summary type and measurement context. Yet the numeric median and full range are not reported in the registry record. A well-described endpoint is not a substitute for its observed values.

The record also illustrates why denominators need to be interpreted by outcome. Enrollment is listed as 13, the primary endpoint was assessed in 8 babies, and the safety group has 12 at risk. These figures refer to different reported contexts. Without participant-flow details or explanations for the denominator differences, it would be misleading to treat them as a single common analysis population.

Early-phase single-group studies can contribute descriptive safety and pharmacologic observations. At the same time, the absence of a concurrent comparator limits causal interpretation. A group’s observed measurements cannot show how those same outcomes would have differed under another condition. This issue is especially relevant when the clinical setting includes cooling and re-warming and when several outcomes are of interest.

The record names multiple aims and outcomes but does not describe a statistical analysis plan, multiplicity handling, or missing-data procedures. That makes it important to distinguish what was registered from what was analyzed and reported. The available information can support transparent description of the design and gaps, but not a reconstruction of unreported analyses or conclusions.

Finally, the listed zero adverse-event counts are useful as a report of what is recorded, but they need context about ascertainment and comparison to support broader conclusions. The statistical lesson is not that the study is uninformative; it is that the strength of an inference depends on the result details, denominator, design, and reporting needed to interpret it.

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 primary outcome is defined, but its numeric median and full range are not reported in the registry record. As a result, the concentration level and its observed variability cannot be assessed. The endpoint description gives useful information about dosing and timing, including the mean number of doses before levels were drawn and the mean time after the last dose, but those details do not recover the missing outcome result.

The primary endpoint was assessed in 8 babies because the others did not have a steady-state trough level performed during cooling. The record does not report an analysis of the missing measurements or whether the infants with measurements differed from those without them. It also does not explain why the safety at-risk count is 12 when enrollment is listed as 13.

The study has no concurrent comparator, and the registry lists no masking. Therefore, descriptive observations cannot establish a treatment contrast, and changes cannot be attributed to clonidine alone. The record does not report a detailed statistical analysis plan, a sample-size justification, interim analyses, or procedures for handling multiplicity. The presence of sample-size planning assumptions does not show that they formed the study’s own design.

The listed safety counts are limited to the reported group and do not include comparative estimates or additional event-ascertainment detail. The registry entries available also do not provide numeric results for the listed secondary outcomes or the other outcome measures. These reporting gaps restrict interpretation of both the study’s pharmacologic endpoint and its broader safety aims.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia — NCT01862250.
• Registry record last updated 2018-01-05; status last verified 2017-12.
• Results first posted 2018-01-05.
• 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

NCT01862250 is a completed Phase I-II, single-group study sponsored by Johns Hopkins University. It enrolled 13 infants with hypoxic-ischemic encephalopathy and investigated intravenous clonidine during therapeutic hypothermia. The group description specifies 1µg/kg/dose either every 6 or 8 hrs from the start of cooling to the end of re-warming.

The primary outcome is steady-state clonidine blood levels during hypothermia, measured in ng/ml and summarized as a median with full range. The record describes trough measurement after 4-7 doses given every 8 hrs, but the numeric blood-level result is not reported in the registry record. Only 8 babies were assessed for that outcome because the others did not have a steady-state trough level performed during cooling.

The registry reports zero serious events, zero other events, and zero deaths among 12 at risk. With a single-group design and no concurrent comparator, these counts and the endpoint description do not establish comparative effects. The analysis plan, missing-data procedures, and results for the listed secondary outcomes are not reported in the registry record.