This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit (NCT02025855), a randomized phase 4 study. The primary outcome is Time to Extubation.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02025855 |
| Phase | Phase 4 |
| Condition | Opioid Use, Unspecified With Withdrawal, Opioid-Induced Disorders, Delirium |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 9 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Henry Ford Health System |
| Results posted | Yes |
2. Clinical Question
Population
Mechanically ventilated patients in a medical intensive care unit who required continuous infusions of sedatives and analgesics were the intended population. The study description says treatment was to begin within 48 hours of admission. The registry record reports 9 enrolled participants, but does not report further demographic or clinical characteristics of the analyzed groups.
Intervention
The intervention was methadone added to standard care. The planned dose was calculated from each participant’s total daily opioid requirements, with a maximum of 60 mg per day. Capsules were to be administered every 8 hours through an enteral feeding tube.
Comparator
The comparator was placebo added to standard care. The placebo capsules contained lactose and were administered every 8 hours through an enteral feeding tube. The number of capsules was to be calculated from opioid requirements so that the capsule count would match between groups.
Primary question
The primary question was whether time to extubation differed between the methadone and placebo groups. The endpoint was recorded as time to extubation in days, with a stated observation timeframe of up to 14 days. The registry reports group medians and inter-quartile ranges, but no inferential comparison.
The trial was designed around a clinical concern described in the registry: patients receiving prolonged intravenous opioids may develop physical dependence, and reducing opioid doses can be associated with withdrawal symptoms. The study description proposed that methadone might help manage this concern while patients remained mechanically ventilated. That rationale is the study’s motivation, not evidence of a treatment effect. The posted results cover a small enrolled group and provide only descriptive primary-endpoint summaries. They do not establish whether the observed group values reflect a reproducible difference or chance variation.
3. Trial Design
NCT02025855, titled Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit, was registered as a phase 4, randomized, parallel-group study with quadruple masking. The registry lists Henry Ford Health System as sponsor. The record reports an enrollment of 9 and a terminated status. The start is recorded as 2014-01 and primary completion as 2017-10. The reason for termination is not reported in the registry record.
Participants were assigned to methadone or placebo, each in addition to standard care. The methadone schedule was based on total daily opioid requirements, with a stated maximum dose of 60 mg per day; placebo capsule counts were also based on opioid requirements. Both were scheduled every 8 hours through an enteral feeding tube. The registry’s description identifies mechanically ventilated medical ICU patients receiving continuous sedative and analgesic infusions as the intended study population, with treatment initiated within 48 hours of admission.
The posted primary-endpoint groups contain 4 participants in the methadone arm and 5 in the placebo arm. The registry does not report the sequence-generation method, allocation concealment procedures, or the specific roles included in quadruple masking. It also does not report the reason for the imbalance in group counts, whether participants discontinued or were excluded from the endpoint analysis, or whether all randomized participants were analyzed as assigned. Those details should not be inferred from the overall enrollment and arm counts.
The registry lists five secondary outcomes: cumulative opioid consumption, level of sedation, corrected QT interval, cumulative antipsychotic use, and cumulative benzodiazepine consumption. Although the record reports six outcome measures, it provides no posted analysis entries. Results for the secondary outcomes are not reported in the registry record. A detailed protocol, analysis plan, sample-size justification, and interim-analysis plan 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.
Overall Study
| Stage | Methadone | Placebo |
|---|---|---|
| STARTED | 4 | 5 |
| COMPLETED | 4 | 5 |
| NOT COMPLETED | 0 | 0 |
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.
| Characteristic | Unit | Methadone | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 4 | 5 | 9 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 3 | 4 | 7 |
| Age, Categorical: >=65 years | Participants | 1 | 1 | 2 |
| Age, Continuous | years | 60 (SD 14.9) | 37 (SD 17.2) | 47 (SD 19.4) |
| Sex: Female, Male: Female | Participants | 0 | 3 | 3 |
| Sex: Female, Male: Male | Participants | 4 | 2 | 6 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 3 | 2 | 5 |
| Race (NIH/OMB): White | Participants | 1 | 3 | 4 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 4 | 5 | 9 |
6. Primary Endpoint
The registry lists the primary outcome as Time to Extubation, measured over Up to 14 days.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | Days |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint was time to extubation, measured in days. It represents the elapsed time until a participant’s breathing tube is removed, as recorded for the study. The registry specifies a timeframe of up to 14 days and reports the endpoint as a median with an inter-quartile range for each group.
Time to extubation is relevant to a trial focused on the duration of mechanical ventilation because it captures how long participants remain intubated before extubation. It is a time-to-event outcome: the event is extubation, while the measured quantity is the time until that event. Such outcomes can be summarized with medians, which describe the middle of the observed time distribution, and inter-quartile ranges, which describe the spread of the central portion of that distribution.
The registry reports a median of 10 days for methadone, with an inter-quartile range of 6.75 to 14, and a median of 4 days for placebo, with an inter-quartile range of 4 to 6. These summaries describe the recorded groups; they do not by themselves quantify uncertainty about a treatment comparison. The record does not report a hazard ratio, confidence interval, or other inferential estimate for the primary endpoint. It also does not describe how participants who had not been extubated by the end of the stated timeframe were handled in the analysis. That analysis detail is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary-endpoint summaries are descriptive. The median time to extubation was 10 days in the methadone group and 4 days in the placebo group. The reported inter-quartile ranges were 6.75 to 14 for methadone and 4 to 6 for placebo. These are observed group summaries among the participants represented in the posted results. They are not an adjusted estimate of the effect of assignment to methadone, and the registry does not report an inferential comparison of the groups.
The number of participants represented is limited: the methadone group has 4 and the placebo group has 5. With so few observations, descriptive summaries can be sensitive to individual participants. The inter-quartile ranges show variation in the recorded times, but they do not resolve how much uncertainty surrounds a comparison between groups. No confidence interval, p-value, hazard ratio, or other sponsor-reported inferential statistic for the primary endpoint appears in the registry record.
Time-to-event outcomes require attention to participants whose event is not observed during the follow-up period. For this endpoint, the event is extubation. A participant who remains unextubated at the end of follow-up may have a censored observation rather than a fully observed time to extubation. The registry states a timeframe of up to 14 days but does not report the number of such participants, the handling of censoring, or the method used to estimate the medians. Those details are not reported in the registry record, so the reported medians cannot be used to reconstruct a time-to-event analysis.
The displayed values alone do not show whether the difference between group summaries is statistically distinguishable from chance variation. Nor do they establish that the groups were comparable in all relevant ways after randomization. Random assignment is intended to support a fair comparison, but the small number enrolled means that chance imbalances can remain. Baseline characteristics and an adjusted analysis are not reported in the registry record.
No recalculated unadjusted comparison is available for this median time endpoint. The registry record identifies the posted data as not estimable for a two-arm comparison using the available summary statistics. Accordingly, there is no basis in the posted results for adding a newly calculated test or effect estimate. The sponsor’s own analysis would take precedence if a discrepancy were reported, but no such discrepancy is reported. No sponsor-reported hazard ratio is available.
The trial status is terminated, and the record reports enrollment of 9. The reason for termination is not reported in the registry record. It would be inappropriate to infer that the termination was caused by the observed endpoint values, recruitment, safety concerns, or any other particular circumstance. The reported summaries are informative as a record of what was observed in these groups, but they do not provide a definitive estimate of the treatment effect or its precision.
9. Statistical Methods Explained
Several statistical ideas help interpret the posted endpoint. The primary outcome is a time-to-event measure: the event is extubation, and the outcome is the time until that event. The registry reports a median and inter-quartile range for each group. It does not report an inferential model or a sponsor-reported hazard ratio, so the interpretation must remain at the level of descriptive summaries.
What does a median describe?
A median is the midpoint of an ordered set of observations. It describes the central location of the observed times without requiring the distribution to be symmetric. This can be useful for time outcomes, which may have a long tail or a concentration of observations at particular times. A median does not describe every participant’s experience, and it does not show how precisely a group comparison has been estimated.
The posted median was 10 days for methadone and 4 days for placebo. These values are group summaries, not individual-level observations. They should not be interpreted as a difference that applies to every participant. The registry does not report the method used to estimate these medians, nor does it provide an inferential comparison accompanying them.
What does an inter-quartile range describe?
An inter-quartile range gives the interval from the lower quartile to the upper quartile: the central half of the observed distribution. It gives information about spread around the median. The reported interval was 6.75 to 14 days for methadone and 4 to 6 days for placebo. An inter-quartile range is not a confidence interval. It describes variation in the observed data rather than the uncertainty in an estimated treatment contrast.
Overlap or non-overlap between inter-quartile ranges is not a substitute for a formal comparison. The ranges are calculated within each group and do not directly estimate the uncertainty of a between-group effect. The registry record provides no confidence interval for a group contrast. A confidence interval, in general, describes the precision of an estimate under the assumptions of the analysis used to calculate it. Without a reported estimate and its interval, readers cannot assess that form of uncertainty for this trial.
Why does censoring matter?
In time-to-event analysis, some participants may not experience the event during the observation period. Their exact event time is then unknown, although it is known that the event had not occurred by their last observation. This is called censoring. Appropriate time-to-event methods can use the observed follow-up while accounting for such incomplete event times. The registry identifies an observation timeframe of up to 14 days, but does not state whether any participants were censored, how censoring was handled, or which estimator was used. These aspects of the analysis are not reported in the registry record.
Common time-to-event methods can estimate event-time distributions or compare groups using a hazard ratio. A hazard ratio summarizes a relative event rate over time under the assumptions of its model; it is not the same as a ratio of medians. No hazard ratio or corresponding uncertainty estimate is reported for this trial. The record’s general description of its endpoint type does not supply a sponsor analysis, and none should be inferred from the group medians alone.
What can randomization and masking support?
Random assignment is intended to reduce systematic differences in prognostic factors between groups, so that a group comparison can be interpreted as a comparison of assigned strategies. It does not guarantee that groups will be identical, especially when only a small number of participants are enrolled. With 4 participants in the methadone group and 5 in the placebo group, chance differences in participant characteristics could affect observed outcomes. Baseline characteristics are not reported in the registry record.
Quadruple masking indicates that the record classified the study as masked at four roles or levels, but it does not identify those roles. Masking can reduce the influence of expectations on care, outcome assessment, or reporting, depending on who is masked and how the process is implemented. The registry does not report the detailed masking procedures or how masking was maintained. Those procedural details cannot be inferred from the classification alone.
Why is there no recalculated comparison?
A simple unadjusted re-calculation requires summary statistics suitable for the chosen comparison. The registry record indicates that the available summaries do not permit a two-arm re-calculation for this median time endpoint. No re-calculated effect, confidence interval, or p-value is therefore presented. This limitation is distinct from a finding of no effect: it means that the posted information does not support that particular calculation.
Planning calculations, when available, are not observed evidence. In general, a sample-size illustration estimates how many participants a hypothetical study might require under specified assumptions. It does not measure the probability that the observed result is true and should not be described as observed power. The registry record does not report a sample-size justification for this trial. Although its planning assumptions mention a two-sided significance level of 0.05, equal allocation, and a normal approximation, no planning participant counts are reported in the posted results. These assumptions do not add inferential evidence to the endpoint summaries.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists five secondary outcomes in addition to the primary endpoint: cumulative opioid consumption, level of sedation, corrected QT interval, cumulative antipsychotic use, and cumulative benzodiazepine consumption. The record reports six outcome measures in total, but no analysis entries are posted. Results for the secondary outcomes are not reported in the registry record.
When a study examines multiple outcomes or multiple comparisons, the chance of at least one apparently notable result can increase if no multiplicity strategy is used. A prespecified analysis plan can state which outcomes are primary, how secondary outcomes will be interpreted, and whether any adjustment is planned. The registry record does not report a multiplicity strategy, the hierarchy for interpreting secondary outcomes, or whether any secondary analyses were conducted. No adjustment should be assumed.
Missing-data handling and analysis populations are also not described. The record does not report whether the primary-endpoint analysis included all randomized participants, only participants with observed extubation times, or another population. It does not report withdrawals, exclusions, missing endpoint values, or the method used to handle censoring. These details are not reported in the registry record.
The absence of posted analysis entries does not establish that no analysis was conducted; it establishes only that such analyses are not reported in the registry record. Without the analysis population, missingness information, and prespecified methods, readers cannot assess how departures from the planned follow-up may have affected the summaries or whether outcome selection influenced what was reported.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Methadone | 0 | 4 | 0.0% |
| Placebo | 0 | 5 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Methadone | 0 of 4 |
| Placebo | 0 of 5 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Methadone | 0 of 4 |
| Placebo | 0 of 5 |
The registry reports serious adverse events for 4 participants at risk in the methadone group and 5 in the placebo group. The number affected by a serious adverse event was 0 in each group. It also reports other adverse events for 4 participants at risk in the methadone group and 5 in the placebo group, with 0 affected in each group. Deaths are reported as 0 in both groups.
These counts describe the events recorded for the participants represented in the safety results. They do not show that the risk of an adverse event is absent. The groups are small, and a count of zero in a small group provides limited information about events that might occur in a larger population or with different follow-up. The registry does not list serious adverse-event terms, and it does not provide additional detail about event ascertainment, severity grading, or follow-up duration for safety outcomes. Those details are not reported in the registry record.
Safety counts should be read separately from the primary endpoint. The absence of reported events does not establish a favorable benefit-harm balance, and the registry does not provide an inferential safety comparison.
12. What the Result Does, and Does Not, Mean
The posted results document a randomized comparison of methadone and placebo in a medical ICU study with 9 enrolled participants. For the primary endpoint, the median time to extubation was 10 days in the methadone group and 4 days in the placebo group. The corresponding inter-quartile ranges were 6.75 to 14 and 4 to 6. These values describe the participants represented in the record; they do not establish why the observed group summaries differed.
The registry does not report a p-value, confidence interval, hazard ratio, or other inferential estimate for the primary endpoint. The available summaries do not support an unadjusted two-arm re-calculation. As a result, the precision of a treatment comparison cannot be quantified from the posted results. The endpoint values should not be treated as proof that assignment to either strategy caused a difference in time to extubation.
The record also does not report the reason the trial was terminated, the analysis population, missing-data handling, baseline characteristics, or the planned statistical analysis. The five listed secondary outcomes have no posted analysis results. These gaps limit interpretation of both the endpoint comparison and the overall evidence recorded for the study. The absence of a posted analysis is not the same as evidence that an analysis found no difference.
The safety record reports no serious adverse events, other adverse events, or deaths among the listed participants. Given the small group counts, these observations cannot establish that adverse events would not occur in a larger study. Taken together, the registry supports a narrow conclusion: it records descriptive endpoint and safety summaries for a small terminated trial, without a reported inferential analysis that establishes the size or precision of a treatment effect.
13. Why This Trial Matters Statistically
This study illustrates why the type of endpoint and the level of reporting matter as much as the observed group summaries. Time to extubation is a time-to-event outcome, and interpretation depends on how follow-up ends for participants who have not yet experienced extubation. A median and inter-quartile range provide a compact description, but they do not replace a time-to-event analysis or its uncertainty estimate.
The trial also shows the limits of drawing broad conclusions from a small randomized study. Randomization is a strong design principle for reducing systematic allocation bias, but it cannot eliminate chance imbalance when few participants are enrolled. Group summaries from 4 and 5 participants are particularly dependent on the observations of the individuals included. The record does not supply baseline characteristics to assess the groups’ composition.
Transparent reporting helps readers distinguish observed data from inferential conclusions. Here, the primary endpoint summaries are present, while a sponsor-reported hazard ratio, confidence interval, p-value, analysis population, missing-data method, and secondary-outcome analyses are not reported in the registry record. This distinction prevents descriptive differences from being mistaken for established evidence about a treatment effect.
The record is also a reminder that study status and outcome results answer different questions. The trial is marked terminated, but the reason is not reported. Neither termination nor the observed endpoint values identify why the study ended. Clear reporting of such context, along with the planned analysis and results, would be needed to support a fuller statistical interpretation.
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 principal limitation is the small enrollment: the posted endpoint groups contain 4 participants assigned to methadone and 5 assigned to placebo. With so few observations, estimates can be imprecise and sensitive to individual outcomes. The registry reports medians and inter-quartile ranges but no confidence interval or inferential group comparison for time to extubation.
The record does not report how time-to-event data were analyzed, whether any participants were censored, or how participants who were not extubated by the end of the stated timeframe were handled. It also does not report the analysis population, missing observations, withdrawals, or protocol deviations. These omissions make it difficult to evaluate whether the endpoint summaries represent all randomized participants and how follow-up contributed to the results.
Baseline characteristics and details of allocation concealment and masking procedures are not reported in the registry record. Although the trial is classified as randomized and quadruple-masked, the record does not identify the masked roles or provide enough detail to assess implementation. The reason for termination is also not reported.
Finally, no analyses are posted for the listed secondary outcomes, and a sample-size justification or full statistical analysis plan is not reported in the registry record. Together, these limitations prevent assessment of the planned multiplicity approach, the intended handling of missing data, and the precision of the treatment comparison. They restrict interpretation to the descriptive values recorded for the small enrolled group.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit — NCT02025855.
- Registry record last updated 2025-12-05; status last verified 2025-12.
- Results first posted 2025-12-05.
- 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.
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18. Record Summary
NCT02025855 was a phase 4, randomized, parallel-group, quadruple-masked study sponsored by Henry Ford Health System. It compared adjunct methadone with placebo for time to extubation among mechanically ventilated medical ICU patients. The registry reports enrollment of 9 and a terminated status; the reason for termination is not reported in the registry record.
The primary endpoint was time to extubation in days, with a timeframe of up to 14 days. The methadone group had a median of 10 days and an inter-quartile range of 6.75 to 14; the placebo group had a median of 4 days and an inter-quartile range of 4 to 6. The record reports no inferential analysis for this comparison. It lists five secondary outcomes, but their results are not reported in the registry record. Serious adverse events, other adverse events, and deaths were reported as 0 in both groups.