Measuring the Amount of Methadone or Morphine in the Blood of Neonates, Infants & Children After Cardiac Surgery.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Measuring the Amount of Methadone or Morphine in the Blood of Neonates, Infants & Children After Cardiac Surgery. (NCT01094522), a randomized phase 1, phase 2 study. The primary outcome is Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide).

2. Clinical Question

The study focused on pain management and drug concentrations during the postoperative period. Its stated rationale was that information about methadone pharmacology in neonates and infants was limited, despite its use in some settings, while fentanyl and morphine were described as commonly used after major surgery. The study was designed to examine pharmacokinetics (PK)—how drug concentrations change over time—and pharmacodynamics (PD)—how drug exposure relates to effects such as pain scores.

The secondary outcomes were FLACC pain scores during the 24-hour study period and the amount of study drug administered during the 24-hour dosing period. Together, these measures address different questions: concentration measurements characterize drug exposure, pain scores describe observed pain assessments, and administered amount records drug use under the study’s PRN approach. The registry record does not report the numerical findings for these outcomes, or how a primary comparison between methadone and morphine was defined.

3. Trial Design

This was a randomized, double-blind, controlled, multisite study with a parallel-group design. It was listed as Phase 1 and Phase 2. The registry record lists an enrollment of 47 and a completed status. The recorded study start is 2010-03, and the primary completion date is 2012-06.

Participants were assigned to methadone or morphine. The description says one half of the study patients would be randomized to each drug. Both groups were to receive a loading dose intravenously, followed by additional intravenous doses on a PRN basis for pain control. Dosing was intended to continue for up to 24 hours during the postoperative course while participants were intubated. The ICU nurse administered the subsequent doses, according to the arm descriptions.

The record lists quadruple masking. It does not explain which groups of people were masked, how masking was maintained, or whether masking was assessed. Randomization can help balance measured and unmeasured characteristics between groups on average, while masking can reduce the influence of treatment knowledge on care or assessment. These are general design principles; the registry record does not give the details of its randomization or masking procedures.

The study population was neonates, infants and children from birth to 5 years of age undergoing cardiac surgery with CPB. The record describes the setting as the intensive care unit after cardiac surgery, during mechanical ventilation. It does not report eligibility criteria beyond the population description, the number of sites, the allocation sequence method, or the planned enrollment rationale. Those details are not reported in the registry record.

The design description identifies a comparison of two drug groups, but the posted record does not provide numerical primary-outcome results, group-level outcome summaries, or an estimate of the treatment contrast. It also does not explain whether the analysis followed randomized assignment or another analysis population. Consequently, the design characteristics can be described, but the effect of assignment cannot be quantified from 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.

Before assignment: Total 47 subjects were enrolled. 7 were withdrawn prior to randomization. 40 were randomized.

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 Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide), measured over 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs.

The primary outcome is titled “Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide).” It is expressed in ng/mL, and the record specifies a median with full range as the summary format. Measurements were scheduled at 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs. These details describe the intended measurement and reporting approach; numerical values are not reported in the registry record.

Maximum concentration is a pharmacokinetic measure. In general, a concentration profile can characterize the amount of drug or metabolite measured in blood over time, while a maximum concentration focuses on the highest measured value during the specified observation period. Including metabolites makes the endpoint broader than a measure of the parent drug alone. The registry title identifies two morphine metabolites, but does not explain the laboratory assay, how a maximum was selected from observations, or whether the endpoint was analyzed separately by randomized group.

A median describes the middle observation in an ordered set, and a full range describes the lowest and highest observations. As a general statistical matter, medians and ranges can communicate a distribution without assuming that values are symmetrically distributed. A range is sensitive to extreme observations and does not by itself show how densely values cluster between its endpoints. The registry record gives no observed median, range, group-specific values, or uncertainty interval for this outcome.

The listed primary outcome concerns morphine and its metabolites, while the study compares methadone and morphine. The record does not clarify how this endpoint was intended to support a comparison between the two assigned groups, nor does it list a parallel methadone concentration endpoint in the primary outcome description. That ambiguity limits interpretation of the endpoint’s role in the planned comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help explain what the registry record can and cannot establish. The descriptions below are general explanations, not claims about unreported procedures in this trial.

What randomization contributes

In a randomized trial, assignment is determined by a chance-based process rather than by a clinician’s or participant’s choice. In general, this can reduce systematic differences between groups at the time of assignment. Randomization does not guarantee that the groups will be identical, particularly in a small study, and it does not remove the need to report group characteristics and outcome data. The registry record states that the study was randomized, but does not report the sequence-generation method, concealment procedure, or baseline characteristics.

The parallel-group description means participants were assigned to one of the two study-drug groups rather than being described as receiving both treatments in sequence. The record names methadone and morphine as the interventions and describes a loading dose followed by PRN intravenous doses for up to 24 hours while participants were intubated. It does not report the exact dose regimens, dose-adjustment rules, or how deviations from the assigned regimen were handled.

What masking can and cannot do

The record lists quadruple masking. As a general principle, masking can reduce the risk that knowledge of assigned treatment influences care, outcome assessment, or reporting. The term alone does not identify which people were masked or describe the practical steps used to conceal assignment. Those details are not reported in the registry record, so the effectiveness of masking cannot be assessed from the record.

How to interpret a median and range

The primary outcome is summarized by a median and full range. In general, the median is the central observation when measurements are ordered, whereas the full range gives the minimum and maximum. These summaries can be useful when data are skewed or when extreme values are clinically or scientifically relevant. They do not show the shape of the distribution, the variability among most participants, or the precision of a comparison between groups. For those purposes, individual data or additional summaries may be needed.

The record identifies serial measurement times from 0 through 24 hrs. Repeated measurements can describe changes in blood concentration over time. A maximum concentration reduces a series of measurements to a single summary for each participant, but interpretation depends on how measurements were obtained and how missing measurements were treated. The registry record does not report those operational or analytical details, nor does it provide observed values.

Pharmacokinetic and pharmacodynamic outcomes

Pharmacokinetics concerns drug exposure and concentration over time; pharmacodynamics concerns effects in relation to exposure. The registry record describes a study of both PK and PD and names the maximum concentration of morphine and metabolites as the primary outcome. It lists FLACC pain scores and the amount of study drug administered as secondary outcomes. These measures capture different aspects of treatment, and none alone supplies a complete account of exposure, effect, or group difference.

In general, an association between concentration and an observed outcome does not by itself establish that the concentration caused the outcome. Such interpretation depends on the analysis, measurement quality, timing, and other factors. The registry record does not report an exposure-response analysis or a statistical model linking concentration to pain scores or drug administration.

Why uncertainty and a planned analysis matter

A treatment-effect estimate describes the contrast being studied, while an uncertainty measure indicates how precisely that contrast has been estimated. In general, confidence intervals are useful because they show a range of estimates consistent with the observed data and stated statistical assumptions. A p-value addresses compatibility with a specified null hypothesis under a specified analysis; it does not measure clinical importance. Neither an estimate nor its uncertainty is reported for the primary outcome in this registry record.

The registry record does not report the statistical analysis plan, the model used for the primary outcome, handling of repeated measurements, adjustments for baseline variables, or the exact contrast of interest. It also does not report interim analyses or a sample-size justification. These omissions mean the planned inferential framework cannot be reconstructed from the record. A design label or an outcome summary format is not enough to identify a statistical test or model.

Planning illustrations are not trial results

In general, sample-size planning illustrations ask how many participants might be needed under stated assumptions about an effect and statistical procedure. They are planning calculations, not evidence about what occurred in a trial, and they do not represent observed power. The registry record does not report the study’s own sample-size rationale or the assumptions used for planning. Any planning illustration should therefore be kept distinct from the randomized enrollment and from observed outcome evidence.

The record lists an enrollment of 47, but this alone does not establish the study’s statistical power or precision. Those depend on the endpoint, variability, analysis method, allocation, and other assumptions. The registry record does not provide enough information to assess these factors or to determine whether the achieved enrollment matched a prespecified target.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome and two secondary outcome descriptions: FLACC pain scores during the 24-hour study period and the amount of study drug administered during the 24-hour dosing period. It also states that there are 4 outcome measures, but does not provide full descriptions or results for all of them. The statistical analysis plan is not reported in the registry record.

Multiplicity is the general statistical issue that arises when several outcomes, time points, or comparisons are examined. If many tests are conducted, the chance of at least one apparently notable result can increase unless the analysis addresses this. Common approaches include identifying a primary comparison in advance or adjusting inference across a family of tests. The record does not report whether multiplicity was considered, what comparisons were planned, or whether any adjustment was used. No multiplicity procedure should be assumed.

Missing-data handling is also not reported. The concentration outcome includes measurements across multiple times, but the record does not state whether all scheduled samples were collected, how missing measurements were handled, or how incomplete follow-up was treated. It does not report missingness for pain scores or drug administration. General methods for missing data rely on assumptions about why observations are absent; without counts and an analysis description, those assumptions cannot be evaluated.

Analysis populations are not described. The record does not say whether results were to be analyzed according to randomized assignment, treatment received, or another defined population. It also does not report participant flow, exclusions from analyses, or the number contributing data to each outcome. These details matter because an analysis set can differ from the total enrollment and can affect how a treatment comparison is interpreted.

The record lists 47 enrolled participants and 20 at risk per group in the adverse-event fields, but does not explain the analysis populations or the relationship between these figures. That discrepancy in scope should not be resolved by assumption. No outcome analysis or missing-data procedure is reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: culture negative sepsis (5.0%), left vocal cord paralysis (5.0%), left pleural effusion (5.0%), acute respiratory failure (5.0%), pulmonary edema requiring re-intubation (5.0%).

The adverse-event fields list serious adverse events and other adverse events separately. For serious adverse events, the record lists 20 participants at risk in the methadone group and 5 affected; for morphine, it lists 20 at risk and 3 affected. For other adverse events, it lists 20 at risk in each group, with 5 affected in the methadone group and 4 in the morphine group. These are counts in the registry record, not estimates adjusted for differences in follow-up or participant characteristics.

The record lists six serious-event terms, each with a frequency of 5.0%: Culture negative sepsis, Left vocal cord paralysis, Left pleural effusion, Acute respiratory failure, Pulmonary edema requiring re-intubation, and Respiratory failure requiring re-intubation. The record does not identify the treatment group for each listed term, so they cannot be assigned to a group from this information. It also does not clarify how those term-level figures relate to the counts of participants affected.

Deaths are listed as null for both groups. A null entry means deaths are not reported in the registry record; it should not be read as a reported count of zero. The record does not provide event timing, duration of follow-up, severity grading beyond the serious/other categories, or a statistical comparison of adverse events. These counts are descriptive and do not establish a causal difference between treatments.

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

The registry record identifies a randomized, double-blind, controlled, multisite study of methadone compared with morphine in neonates, infants and children from birth to 5 years undergoing cardiac surgery with CPB. It describes a postoperative setting in which participants were intubated and received a loading dose followed by PRN intravenous dosing for up to 24 hours. It also identifies a pharmacokinetic primary outcome and pain scores and amount of study drug as secondary outcomes.

What the record does not provide is the numerical primary-outcome result, the numerical secondary-outcome results, or a statistical estimate comparing the assigned groups. There is no reported confidence interval or p-value for those outcomes. Accordingly, the record does not show how concentrations, pain scores, or drug amounts differed between groups, how precise any difference might have been, or whether an observed difference was compatible with chance under a specified analysis.

The adverse-event counts provide limited descriptive information, but they do not fill the gap in outcome analyses. The number at risk is listed as 20 in each group for serious and other adverse events, while the overall enrollment is 47; the record does not explain the relationship between these quantities. Serious-event terms are listed with percentages but are not attributed to treatment groups. Death entries are not reported rather than stated as zero.

These limitations concern what can be concluded from the registry record, not what may have been measured or analyzed outside it. The registry record does not include the study’s statistical plan, analysis populations, missing-data methods, or sample-size justification. Without those details and without numerical results, neither the size nor the precision of a treatment contrast can be evaluated. The design and stated objectives describe the intended investigation; they do not by themselves demonstrate an effect in either direction.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines a randomized, masked, parallel-group comparison with a population described as neonates, infants and children from birth to 5 years undergoing cardiac surgery. The study’s stated focus on PK and PD makes clear that the question involves both measured drug exposure and clinical assessments such as pain scores. Such outcomes address different parts of the research question and require explicit definitions and analysis plans.

The primary outcome is a maximum blood concentration of morphine including two named metabolites, summarized by a median and full range across repeated measurement times. That specification raises important interpretive questions: how measurements over time are reduced to a maximum, how incomplete profiles are handled, and how an outcome named for morphine relates to a randomized comparison with methadone. The registry record does not answer those questions, making transparent outcome definitions and analysis reporting especially important.

The record also illustrates why design information and result reporting need to be read separately. Randomization, masking, and parallel allocation describe methods intended to support a fair comparison. They do not reveal the observed group values or the uncertainty around a treatment contrast. A numerical result with an interval estimate and a clear analysis population would be needed to evaluate precision and direction.

Finally, the enrollment count and adverse-event risk counts are not reconciled in the record, and the statistical plan is not reported. These gaps limit assessment of the population contributing to each outcome and of the methods used to handle multiple outcomes, repeated measurements, and missing data. The trial’s subject matter makes careful reporting of those elements important, but the record does not supply enough information to evaluate them.

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.

Several trial-specific limitations arise from the information recorded. The primary outcome is described as the maximum concentration of morphine and its metabolites, but the comparison is between methadone and morphine. The record does not explain whether the concentration outcome applies to one randomized group, both groups, or a particular planned contrast. It also does not list a primary methadone concentration outcome. This leaves the relationship between the endpoint and the randomized comparison unclear.

The record gives a measurement schedule extending through 24 hrs but does not report the collection method, assay details, completeness of sampling, or the rule for deriving a maximum from serial measurements. These details are relevant to interpreting a concentration summary. The record does not provide observed medians or full ranges, so neither the values nor their distribution can be assessed.

Although the study is described as multisite, the number of sites and any site-level considerations are not reported. Eligibility criteria beyond the age and cardiac-surgery description, baseline characteristics, and participant flow are not reported in the registry record. The record also does not describe exact dosing regimens or how PRN administration varied across participants.

For outcomes, the record lists FLACC pain scores and amount of study drug as secondary outcomes but gives no numerical findings. It does not report the statistical analysis plan, analysis populations, missing-data methods, interim analyses, or the sample-size justification. It does not explain the relationship between enrollment of 47 and the adverse-event fields listing 20 at risk in each group. The serious-event terms are not assigned to treatment groups, and the death fields are null. These omissions prevent a complete assessment of efficacy, precision, safety comparisons, and the populations represented by each result.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Measuring the Amount of Methadone or Morphine in the Blood of Neonates, Infants & Children After Cardiac Surgery. — NCT01094522.
• Registry record last updated 2017-09-18; status last verified 2017-08.
• Results first posted 2017-08-09.
• 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

NCT01094522 is a completed, randomized, double-blind, controlled, multisite, parallel-group study listed as Phase 1 and Phase 2. Enrollment is listed as 47. The recorded start is 2010-03, and primary completion is 2012-06. The study compared intravenous methadone with intravenous morphine in neonates, infants and children from birth to 5 years undergoing cardiac surgery with CPB and mechanical ventilation.

The primary outcome was maximum concentration of morphine including morphine-3-glucuronide and morphine-6-glucuronide, expressed in ng/mL and summarized by median and full range. The record specifies sampling times from 0 through 24 hrs. Secondary outcomes were FLACC pain scores and amount of study drug during the 24-hour period. Numerical results and statistical analyses are not reported in the registry record.

Serious adverse events were recorded for 5 of 20 participants at risk in the methadone group and 3 of 20 in the morphine group; other adverse events were recorded for 5 of 20 and 4 of 20, respectively. The record lists serious-event terms but does not assign them to treatment groups. Deaths are not reported in the registry record.