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 A Pilot Trial to Determine the Effective N-acetylcysteine Dose for Opioid Reduction for Spine Surgery. (NCT04562597), a randomized phase 1, phase 2 study. The primary outcome is Opioid Consumption 12 Hours Post Operative.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04562597 |
| Phase | Phase 1, Phase 2 |
| Condition | Surgery |
| Allocation | Randomized |
| Design model | Sequential |
| Masking | Triple |
| Enrollment | 50 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Medical University of South Carolina |
| Results posted | Yes |
2. Clinical Question
Population
Patients undergoing spine surgery are the intended population. The registry describes postoperative opioid consumption as the outcome and lists Surgery as the condition. It does not report more detailed eligibility criteria, the characteristics of enrolled participants, or how closely the enrolled group represents patients undergoing spine surgery more broadly.
Intervention
The intervention is intravenous N-acetylcysteine (NAC). The planned dose-finding stage included NAC 50 mg/kg, 100 mg/kg, and 150 mg/kg, alongside placebo. The registry describes a subsequent stage in which an optimal dose would be selected for comparison with placebo. The posted primary outcome groups are labelled Placebo and N-acetylcysteine (NAC); the dose represented by the NAC outcome group is not stated in that result label.
Comparator
The comparator is placebo. The trial record describes placebo in both the dose-response stage and the comparison intended to estimate opioid consumption for the selected optimal NAC dose. The record does not give a matching dose label alongside the posted NAC primary outcome estimate.
Primary question
The primary endpoint is opioid consumption 12 hours postoperatively, measured in IV morphine mg equivalents. The stated aim is to determine an optimal NAC dose for opioid reduction after spine surgery and estimate the difference in opioid consumption between placebo and that selected dose. The posted results give separate group means with confidence intervals, rather than a direct estimate of the between-group difference. They therefore describe the reported group estimates but do not, on their own, quantify the treatment contrast or its uncertainty.
3. Trial Design
The registry describes a randomized, triple-masked, sequential pilot trial in Phase 1 and Phase 2. Its status is completed, and the listed enrollment is 50. The sponsor is the Medical University of South Carolina. The registered objective combines dose selection with a later comparison: first identify an NAC dose using a dose-response stage, then estimate opioid consumption for placebo versus the selected dose.
For the dose-response stage, the arm descriptions specify that 5 participants would be randomized to each of four groups: placebo and NAC 50 mg/kg, 100 mg/kg, or 150 mg/kg. The record then describes 15 additional participants randomized to the optimal NAC dose, alongside 15 participants randomized to placebo for the comparison of opioid consumption. The optimal-dose description is truncated in the registry record, so its remaining details are not reported in the registry record. The arm descriptions express the planned allocation; they do not establish how many participants completed each stage or contributed data to each outcome.
The primary outcome is opioid consumption 12 hours postoperatively, in IV morphine mg equivalents. The record also lists opioid consumption every 6 hours postoperatively as a secondary outcome. Its primary-outcome description says that results are reported as mean estimates with 95% confidence intervals from a linear mixed model of opioid consumption over time. It identifies treatment group, postoperative time, and an interaction between treatment group and time as model terms, although the model description is incomplete. Further details of the sequence used to select the dose, randomization procedures, masking procedures, and analysis plan are not reported in the registry record.
The posted primary outcome results list 20 participants in each of the Placebo and N-acetylcysteine (NAC) groups. Those endpoint group counts are distinct from the planned dose-finding allocation described in the arm descriptions. The record does not explain the relationship between the dose-stage groups and the posted primary outcome groups, or identify the dose in the NAC results label.
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 | Period 1: NAC (0mg/kg) | Period 1: NAC (50mg/kg) | Period 1: NAC (100mg/kg) | Period 1: NAC (150mg/kg) | Period 2: NAC (0mg/kg) | Period 2: NAC (150mg/kg) |
|---|---|---|---|---|---|---|
| STARTED | 5 | 5 | 5 | 5 | 15 | 15 |
| COMPLETED | 5 | 5 | 5 | 5 | 15 | 15 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Primary and secondary outcomes were only be evaluated for the placebo and optimal NAC groups. Data are reported as mean (95% CI) estimated from a linear mixed model of opioid consumption over time including main effects for treatment group, postoperative time, and the interaction between treatment group and postoperative time and a random subject effect.
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 | NAC (0mg/kg) | NAC (50mg/kg) | NAC (100mg/kg) | NAC (150mg/kg) | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 20 | 5 | 5 | 20 | 50 | |
| Age, Continuous | years | 58.6 (SD 12.8) | 68.4 (SD 8.21) | 71.6 (SD 7.54) | 67.4 (SD 6.62) | 64.4 (SD 10.2) |
| Sex: Female, Male: Female | Participants | 9 | 2 | 2 | 7 | 20 |
| Sex: Female, Male: Male | Participants | 11 | 3 | 3 | 13 | 30 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 4 | 2 | 0 | 4 | 10 |
| Race (NIH/OMB): White | Participants | 15 | 3 | 5 | 16 | 39 |
| Race (NIH/OMB): More than one race | Participants | 1 | 0 | 0 | 0 | 1 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 20 | 5 | 5 | 20 | 50 |
| Home opioid use (yes) | participants | 5 | 2 | 1 | 5 | 13 |
6. Primary Endpoint
The registry lists the primary outcome as Opioid Consumption 12 Hours Post Operative, measured over 12 hours.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | IV morphine mg equivalents |
| Endpoint classification | Continuous Endpoint |
The primary endpoint measures opioid consumption during the 12 hours after surgery, expressed in IV morphine mg equivalents. A common unit allows opioid consumption to be represented on one scale when interpreting the outcome. The registry describes this as postoperative consumption and names the endpoint at the 12-hour time point. It also states that the estimate comes from a linear mixed model of opioid consumption over time, rather than describing only a simple standalone measurement. The precise way the model-derived estimate maps to the named 12-hour endpoint is not fully specified in the registry record.
Opioid consumption is relevant to the trial’s stated objective because the study aims to identify an NAC dose associated with reduced postoperative opioid use and estimate consumption under placebo versus the selected dose. The record also lists opioid consumption every 6 hours postoperatively as a secondary outcome, which concerns the course of consumption over postoperative time. Values for that secondary outcome are not reported in the registry record.
For a continuous endpoint, a group mean gives an estimate of the average outcome in that group. It does not describe every participant’s consumption or the spread of individual values. The posted primary outcome results give means and 95% confidence intervals for placebo and NAC. They do not give a direct difference between the group means, a confidence interval for that difference, or a p-value. Those omissions limit what can be concluded about the size and precision of the comparison that motivated the trial.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary endpoint estimate is 19.4 IV morphine mg equivalents for placebo, with a 95% confidence interval from 10.8 to 28.0. For N-acetylcysteine (NAC), the mean is 15.6 IV morphine mg equivalents, with a 95% confidence interval from 7.02 to 24.2. The NAC point estimate is lower than the placebo point estimate. These are separate group estimates; the registry does not post a direct estimate of the difference between them.
A confidence interval describes uncertainty around an estimated quantity under the statistical method used. It is not an interval containing every participant’s outcome, nor does it give the probability that the true value lies within that particular interval. The posted intervals span a range of possible mean values, and the intervals overlap. That visual relationship is not a substitute for a confidence interval or test of the between-group contrast. In particular, the registry does not provide the standard error, confidence interval, or p-value for the difference, so the precision of that comparison cannot be read directly from the separate group intervals.
The primary outcome description says the estimates came from a linear mixed model of opioid consumption over time, with treatment group, postoperative time, and their interaction among the stated terms. This matters because estimates from a model that uses observations over time need not be identical to a simple calculation from one raw measurement per participant. The full model specification is incomplete, and the registry record does not report additional terms, covariance assumptions, handling of missing observations, or the exact contrast used to obtain the posted group values.
The outcome group labels show 20 participants for placebo and 20 for NAC. The record does not identify the NAC dose in that results label. It also does not explain how the posted comparison relates to the planned dose-finding and subsequent optimal-dose stages. Consequently, the posted estimates cannot be attributed to a particular listed NAC dose based on the results label alone.
The registry lists two outcome measures and one secondary outcome, but it does not post values for opioid consumption every 6 hours postoperatively. It lists zero analysis records. That does not erase the primary outcome estimates, but it means the registry does not supply a fuller set of statistical analyses such as a treatment contrast or its inferential test. No p-value or conclusion about statistical significance is reported. The record does not flag a discrepancy between its posted results and its own analysis.
Overall, the posted numbers describe estimated average opioid consumption for the two labelled groups, with uncertainty around each mean. They do not by themselves establish the magnitude or precision of the placebo-versus-NAC difference, identify the optimal dose, or show whether the estimates represent a particular NAC dose.
9. Statistical Methods Explained
The endpoint is continuous: opioid consumption is measured on a numerical scale in IV morphine mg equivalents. The registry characterizes the reported measure as a mean. A mean summarizes the central level of a group’s measurements, but does not show how widely individual measurements vary or whether a small number of high values influence the average. No participant-level distribution or measure of spread is posted for the primary endpoint.
What does a confidence interval communicate?
The registry reports a 95% confidence interval for each group mean. In general, a confidence interval expresses the uncertainty associated with an estimate under a specified statistical procedure. Repeated use of a procedure under its assumptions would produce intervals that cover the underlying quantity at the stated rate. For an individual interval, it is not correct to say there is a 95% probability that the fixed underlying mean lies inside it. The interval also is not a prediction range for individual participants.
For placebo, the reported mean is 19.4 and its 95% confidence interval runs from 10.8 to 28.0. For NAC, the reported mean is 15.6 and its 95% confidence interval runs from 7.02 to 24.2. These intervals express uncertainty around their respective group means. The registry does not report a confidence interval for the difference between groups. Separate confidence intervals cannot serve as an exact replacement for an interval around a contrast, because the uncertainty of a contrast depends on the statistical relationship between the estimates as well as their individual uncertainty.
Why use a linear mixed model?
In general, a mixed model can represent outcomes measured repeatedly within participants while accounting for the fact that measurements from the same person may be related. It can also model how average outcome patterns vary over time and between groups. The registry says that a linear mixed model was used for opioid consumption over time and names treatment group, postoperative time, and an interaction between treatment group and time. An interaction allows the pattern over time to differ between treatment groups. The registry’s description is truncated, so the full model and the interpretation of its terms are not reported in the registry record.
The record does not state the covariance structure, whether additional participant-level terms were used, how time was coded, or which model-derived estimate corresponds exactly to the 12-hour endpoint. It also does not state the method used to calculate the confidence intervals. These details can affect how an estimate is interpreted and how its uncertainty is quantified. They should not be inferred from the name of the model alone.
How does the sequential dose-finding design affect interpretation?
The registered design combines a dose-response stage with a later comparison involving an optimal NAC dose. The dose-response stage is described as using placebo and three NAC doses. The next stage is described as adding participants in an optimal-dose group and a placebo group. In general, sequential designs can use information gathered in an earlier stage to determine what is studied later. The registry identifies the design as sequential and describes this intended structure, but does not report the dose-selection rule, the timing of the decision, or whether selection used a prespecified statistical procedure.
Because dose selection and estimation are linked in the stated objective, the method used to select the dose matters for interpreting later estimates. The record does not explain whether uncertainty from dose selection was incorporated into the reported estimates or what comparison was prespecified for the primary analysis. It also does not identify the NAC dose represented by the posted NAC outcome group. Therefore, the posted group means cannot be used to reconstruct the dose-response curve or identify which dose was selected.
What can and cannot be inferred from the posted estimates?
The group means describe the estimated averages for placebo and NAC, and their confidence intervals show uncertainty around those averages. The NAC point estimate is lower, but the registry does not give the direct treatment contrast. A direct contrast would express the estimated difference between groups on the endpoint scale, with its own uncertainty. Without that contrast, the size and precision of the comparison remain unreported. A p-value is also not reported, so the posted results do not establish whether a statistical test rejected a null hypothesis.
General statistical practice distinguishes a point estimate from evidence about its precision. A numerical difference in point estimates alone does not reveal how reliably the groups differ, and a confidence interval for each group mean is not a confidence interval for their difference. Nor does a nonsignificant result, if one were reported, establish equality. Here, no significance test for the comparison appears in the registry record, so neither significance nor equivalence should be asserted.
The registry lists zero analysis records while posting outcome estimates. The record does not provide details that would allow the full statistical analysis to be reproduced, including the model specification, analysis population, missing-data approach, and the contrast calculation. General explanations of mixed models and confidence intervals describe statistical concepts; they do not fill in those unreported trial methods.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures: the primary outcome of opioid consumption 12 hours postoperatively and the secondary outcome of opioid consumption every 6 hours postoperatively. It posts primary outcome estimates for placebo and NAC, but values for the secondary outcome are not reported in the registry record. The record lists zero analysis records. It does not report a multiplicity strategy, such as an adjustment for testing multiple outcomes or multiple comparisons, and no p-values are posted.
Multiplicity can arise when several outcomes, time points, doses, or contrasts are examined. In general, conducting multiple statistical tests can increase the chance that at least one result appears unusually strong by chance. Whether and how that issue was handled in this trial is not reported in the registry record. The sequential dose-selection objective makes the dose-selection procedure relevant to inference, but the registry does not state its decision rule or how selection uncertainty was addressed. No interim analysis plan is reported in the registry record.
The primary outcome description says that results are reported for the placebo and optimal NAC groups. The posted endpoint labels are Placebo and N-acetylcysteine (NAC), with 20 participants in each. The NAC dose is not identified in that outcome label. The registry does not specify further analysis populations, how many participants were randomized to each analysis group, or how exclusions from analysis were handled.
Missing-data methods and the amount or pattern of missing endpoint data are not reported in the registry record. It is therefore not possible to determine from the record whether all randomized participants contributed to the primary endpoint, how incomplete repeated measurements were handled, or whether sensitivity analyses were performed. The analysis population should not be assumed to be either all randomized participants or only those with complete measurements.
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 |
|---|---|---|---|
| Placebo | 0 | 20 | 0.0% |
| NAC 50 mg/kg | 0 | 5 | 0.0% |
| NAC 100 mg/kg | 0 | 5 | 0.0% |
| NAC 150 mg/kg | 0 | 20 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Placebo | 0 of 20 |
| NAC 50 mg/kg | 0 of 5 |
| NAC 100 mg/kg | 0 of 5 |
| NAC 150 mg/kg | 0 of 20 |
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 |
|---|---|
| Placebo | 0 of 20 |
| NAC 50 mg/kg | 0 of 5 |
| NAC 100 mg/kg | 0 of 5 |
| NAC 150 mg/kg | 0 of 20 |
The registry safety figures list zero serious adverse events among 20 participants in the Placebo group, 5 in NAC 50 mg/kg, 5 in NAC 100 mg/kg, and 20 in NAC 150 mg/kg. The deaths column lists zero for each of those groups. The registry also lists zero other adverse events in each of the same groups. No serious adverse event terms are listed.
These are event counts within the groups and at-risk counts recorded for safety reporting. A zero count means that no event of that category was recorded for the listed group in this registry entry. It does not establish that an event cannot occur, and it does not show that the groups have identical safety profiles. With a pilot trial, safety counts are descriptive and can be limited in their ability to characterize uncommon outcomes. No uncertainty intervals or comparative safety analysis are reported in the registry record.
The group sizes in the safety listing differ across the dose groups and should not be combined with the primary outcome group labels without further information. The record does not explain how these safety categories relate to the sequential stages or to the 20-person NAC outcome group. The safety figures therefore describe the reported categories and counts, not a complete account of all possible safety outcomes.
12. What the Result Does, and Does Not, Mean
The posted results describe estimated mean postoperative opioid consumption for placebo and NAC. The placebo mean is 19.4 IV morphine mg equivalents, with a 95% confidence interval from 10.8 to 28.0. The NAC mean is 15.6 IV morphine mg equivalents, with a 95% confidence interval from 7.02 to 24.2. The point estimate for NAC is lower, but the registry does not provide the estimated difference between groups or its confidence interval.
That distinction is central. Separate group means do not directly quantify the treatment contrast, and separate confidence intervals do not provide the uncertainty around that contrast. The registry also does not post a p-value for the comparison. The estimates therefore do not establish whether the groups differ statistically, how precisely any difference is estimated, or whether the results are compatible with a range of clinically important contrasts.
The stated objective includes identifying an optimal NAC dose. The registry lists a dose-response stage and a later optimal-dose comparison, but the posted outcome group label does not name a dose, and the dose-selection procedure is not described. The results therefore do not identify which dose was optimal or show how opioid consumption varied across the listed doses. Values for the listed secondary outcome, opioid consumption every 6 hours postoperatively, are not reported in the registry record.
The results also do not establish that NAC reduces opioid consumption, or that it has no effect. Such conclusions would require a clearly specified comparison and appropriate uncertainty estimates, which are not posted for the primary contrast. The trial record describes a pilot study and provides group estimates that can be read descriptively. It does not provide the information needed to draw a definitive conclusion about the comparative effect or to generalize the result beyond the study population.
The safety counts are likewise descriptive. No serious adverse events or deaths are listed in the groups shown, but the registry figures do not establish the absence of risk. Missing details about the analysis population, missing data, and the relation between sequential stages further limit interpretation of the posted estimates.
13. Why This Trial Matters Statistically
This trial is statistically interesting because its objective links dose selection with estimation of a later comparison. The record describes a dose-response stage with placebo and three NAC doses, followed by a comparison involving an optimal dose and placebo. In this kind of design, the method used to choose a dose is important: an estimate after selection may have different uncertainty from an estimate for a dose specified in advance. The registry identifies the study as sequential but does not report the selection rule or how dose selection entered the analysis.
The record also illustrates why group estimates and treatment contrasts are not interchangeable. It posts a mean and confidence interval for each labelled group, but not a direct between-group difference, its confidence interval, or a p-value. Readers can compare the point estimates descriptively, but cannot use them as a substitute for the planned estimate of the difference in opioid consumption. The distinction is especially important when the stated scientific objective concerns a comparison rather than the separate average in each group.
The stated use of a linear mixed model is relevant because the endpoint is described as opioid consumption over time. Such models can account for relationships among repeated measurements and represent patterns that may differ between groups. Yet the available model description is incomplete. Information about the model structure and missing observations is necessary to understand exactly what the estimates represent and how their uncertainty was obtained.
Finally, the registry record separates the planned allocation from the posted result labels without explaining their relationship. The dose in the NAC outcome group is not identified, and secondary-outcome values are absent. These gaps show why a pilot result should be read in light of its design, estimand, and reporting detail, rather than as a standalone numerical comparison.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The registry record does not report the direct primary treatment contrast, a confidence interval for that contrast, or a p-value. As a result, the comparative estimate that matches the trial’s stated objective cannot be evaluated from the posted primary outcome values. The reported mean and confidence interval for each group provide descriptive information, but do not resolve that limitation.
The NAC group in the primary results is not labelled with a dose. Although the design describes NAC 50 mg/kg, 100 mg/kg, and 150 mg/kg during dose finding and a later optimal-dose comparison, the record does not identify which dose underlies the posted NAC mean. It also does not describe the dose-selection rule or connect the dose-finding data to the final comparison. This limits interpretation of both dose response and the intended optimal-dose estimate.
The endpoint description refers to opioid consumption 12 hours postoperatively and also says estimates were obtained from a linear mixed model of consumption over time. The exact model-derived quantity for the primary endpoint is not fully specified. The model description is truncated, and details such as covariance structure, time coding, additional terms, and confidence-interval construction are not reported in the registry record.
The registry does not report participant characteristics, eligibility criteria, the number completing the endpoint, missing-data patterns, analysis populations, or methods for handling missing observations. It lists a secondary outcome but posts no values for it. Nor does it report a multiplicity plan, interim analyses, or the statistical procedure used for dose selection. These are reporting limitations; the record does not establish whether such procedures were absent from the study or simply not recorded in the registry.
Safety counts are reported across groups, but the record does not explain their relationship to the sequential design or to the endpoint analysis groups. The listed zero counts should therefore be interpreted as the registry’s reported event counts, not as proof that adverse outcomes cannot occur.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Pilot Trial to Determine the Effective N-acetylcysteine Dose for Opioid Reduction for Spine Surgery. — NCT04562597.
- Registry record last updated 2023-02-14; status last verified 2023-01.
- Results first posted 2023-02-14.
- 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
The registry record describes NCT04562597 as a completed randomized, triple-masked, sequential Phase 1 and Phase 2 pilot trial with listed enrollment of 50. Its objective was to determine an optimal intravenous NAC dose for opioid reduction after spine surgery and estimate opioid consumption for placebo versus the selected dose.
The primary endpoint is opioid consumption 12 hours postoperatively in IV morphine mg equivalents. Posted mean estimates are 19.4 for placebo and 15.6 for N-acetylcysteine (NAC), with respective 95% confidence intervals of 10.8 to 28.0 and 7.02 to 24.2. Each posted outcome group lists 20 participants. The NAC dose is not named in the result label, and no direct treatment contrast or p-value is reported.
The record lists opioid consumption every 6 hours postoperatively as a secondary outcome, but its results are not reported in the registry record. Safety listings show zero serious adverse events and zero deaths in the reported groups. Further details on the analysis population, missing data, model specification, multiplicity, and dose-selection procedure are not reported in the registry record.