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 N-acetylcysteine and NMDA Antagonist Interactions (NCT00611897), a randomized phase 1, phase 2 study. The primary outcome is Target P300.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00611897 |
| Phase | Phase 1, Phase 2 |
| Condition | Cognitive Dysfunction |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Triple |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Yale University |
| Results posted | Yes |
2. Clinical Question
Population
The brief summary describes healthy humans, and the primary outcome population is listed as per protocol. The condition field lists cognitive dysfunction, so the record contains both that condition label and a description of healthy participants. It does not report further eligibility details or a fuller account of the analyzed population.
Intervention
The registered intervention label is N-acetylcysteine and ketamine. The arm description for active N-acetylcysteine specifies oral capsules given in divided doses: 2000 mg followed by 1000 mg 2 hours later. The description also refers to a saline bolus and infusion. The arm text is incomplete, and details beyond the text in the registry record are not reported there.
Comparator
The registered comparator is placebo and ketamine. The placebo arm description specifies oral capsules in divided doses: 2000 mg followed by 1000 mg 2 hours later, followed by a saline bolus and infusion. The registry record does not give a complete account of the treatment procedures in the arm descriptions.
Primary question
The study tests whether N-acetylcysteine changes the cognitive effects associated with NMDA antagonism, assessed in part through event-related potentials. The primary endpoint is Target P300, measured daily. The record does not report a numerical comparison of Target P300 between treatment conditions, so the magnitude, direction, and precision of any difference cannot be determined from the registry record.
The intervention labels define the registered comparison, while the brief summary frames the scientific question around extrasynaptic mechanisms and cognitive effects of NMDA antagonism. That framing is a hypothesis, not a reported finding. The registry record describes a randomized, triple-masked crossover design, in which participants receive treatments in different sequences. Such a design can support within-participant comparisons, but the record does not provide enough information to reconstruct the full sequence, timing, or analysis.
3. Trial Design
The registry record describes a randomized, triple-masked crossover study in Phase 1 and Phase 2, with enrollment of 16. Its status is completed. The listed start date is 2006-01 and the primary completion date is 2011-02. The sponsor is Yale University. These administrative details identify the registered study but do not supply an outcome result.
A crossover design assigns treatment sequences so that participants receive more than one condition over the course of a study. The adverse-event group labels identify the sequences as Day 1 placebo NAC followed by Day 2 active NAC, or Day 1 active NAC followed by Day 2 placebo NAC. Those labels indicate an order of NAC conditions; they do not provide a complete description of every treatment or procedure on each day. The registered intervention labels name N-acetylcysteine and ketamine for the active condition, and placebo and ketamine for the comparator.
Randomization concerns assignment to a treatment sequence. Triple masking means the registry classifies the study as masked at three levels, but it does not identify those roles or describe how masking was maintained. The full randomization procedure, allocation concealment, and masking procedures are not reported in the registry record.
The arm descriptions state that capsules were administered orally in divided doses, with 2000 mg followed by 1000 mg 2 hours later. They also describe a 1-min bolus of normal saline followed by a 70-minlong saline infusion, during which behavioral, cognitive, and ERP data were collected. The arm descriptions end mid-sentence, so the full protocol and procedural details are not reported in the registry record.
The brief summary describes testing the hypothesis that extrasynaptic mechanisms are linked with cognitive effects of NMDA antagonism, using event-related potentials in healthy humans. The condition field separately lists cognitive dysfunction. The record does not explain this difference in wording or give additional information that would resolve it. It also does not report the rationale for the enrollment target or the detailed statistical plan.
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: All subjects gave written informed consent. They had no personal or family history of psychiatric or substance abuse disorders. A total of 43 subjects consented; 21 of them never initiated the study due to ineligibility or scheduling conflicts, and 6 subjects dropped out. Sixteen subjects completed the study procedures.
Day 1: Initial Treatment
| Stage | Day 1: Active NAC; Day 2: Placebo NAC | Day 1: Placebo NAC; Day 2: Active NAC |
|---|---|---|
| STARTED | 8 | 8 |
| COMPLETED | 8 | 8 |
| NOT COMPLETED | 0 | 0 |
Day 2: Crossover Treatment
| Stage | Day 1: Active NAC; Day 2: Placebo NAC | Day 1: Placebo NAC; Day 2: Active NAC |
|---|---|---|
| STARTED | 8 | 8 |
| COMPLETED | 8 | 8 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Per protocol
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 | Overall Sample |
|---|---|---|
| Participants analysed | 16 | |
| Age, Continuous | years | 27.0 (SD 5.6) |
| Sex: Female, Male: Female | Participants | 3 |
| Sex: Female, Male: Male | Participants | 13 |
6. Primary Endpoint
The registry lists the primary outcome as Target P300, measured over daily.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | microvolts |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is Target P300, a continuous measure reported in microvolts. The record specifies least-squares means with standard errors and identifies the population as per protocol. Measurements were obtained from the Fz, Cz, and Pz electrodes, and the stated timeframe is daily.
The stimulus description includes target tones at 1000 Hz lasting 500 ms and novel environmental sounds lasting approximately 250 ms. Participants were instructed to respond to target sounds by pressing a button with the index finger of their dominant hand. Standard stimuli were click trains at 20, 30, or 40 Hz in the first, second, and third runs, respectively. All stimuli were presented at 80 dB SPL. The record says that the auditory steady-state EEG driving data from the standard stimuli would be presented in a separate report; that report's results are not included in the registry record.
General: P300 is an event-related potential: a brain electrical response measured in relation to a stimulus. Target and novel-stimulus tasks can be used to study attention and stimulus processing. An electrode records electrical activity at a specified scalp location; measurements at different locations can therefore describe the response from different sites. These general features explain why P300 can serve as a cognitive endpoint, but they do not establish what the trial found.
The registry record does not report the Target P300 least-squares means, standard errors, treatment contrast, confidence interval, or test result. Consequently, the size and precision of the treatment comparison cannot be assessed from the endpoint description alone.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive limitation is that the registry record describes the primary outcome but does not report its numerical results. It identifies Target P300 as a daily continuous measure and gives the intended summary as a least-squares mean with a standard error. It does not provide those summaries by treatment condition, a treatment contrast, a confidence interval, or a significance test. The record therefore does not establish the direction, magnitude, or precision of a difference in Target P300.
The record lists 5 outcome measures and 0 analyses. The primary outcome description refers to measurements at Fz, Cz, and Pz and gives a daily timeframe. A note in the record indicates that the primary outcome has several categories or time points and was not reduced to a single comparison. Without the estimates and a clearly specified contrast, a reader cannot determine which electrode, day, or summary is intended to represent the main treatment comparison. The missing numerical results cannot be reconstructed from the endpoint description.
The study’s stated hypothesis concerns extrasynaptic mechanisms and cognitive effects of NMDA antagonism, with event-related potentials used as evidence. A hypothesis describes the question motivating a study; it is not evidence that the proposed mechanism was confirmed. No mechanistic result, behavioral result, or quantitative ERP result is reported in the registry record. The listed secondary outcomes are Mismatch Negativity intensity, frequency, and duration, but their numerical results are also not reported in the registry record.
The trial is described as randomized, triple-masked, and crossover. Those design labels describe how the study was organized, not whether the treatment conditions differed on an outcome. In general, crossover comparisons may use within-participant information, but the registry record does not report the analysis model or explain how the treatment sequence, day, period, or possible carryover effects were handled. It is therefore not possible to judge whether the analysis accounted for those design features.
The primary outcome population is per protocol. The registry record does not report the number included in that population, participant flow, exclusions, or the handling of missing outcome measurements. Enrollment of 16 does not establish how many contributed data to each outcome analysis. Nor does the record explain whether the per-protocol analysis was prespecified or how it relates to any other analysis population.
The adverse-event counts are separate from the efficacy question. They describe reported events by sequence group, not a comparison of Target P300. The record lists no serious adverse events in either group and reports other adverse events in one group. These counts do not fill the gap in the primary outcome results and do not support conclusions about the treatment effect on cognition.
In practical terms, the registry record supports describing the study question, design, endpoint, and some safety counts. It does not support a quantitative assessment of the primary outcome. Any conclusion about whether the treatment conditions produced a difference, and how precisely that difference was estimated, would require outcome results that are not reported in the registry record.
9. Statistical Methods Explained
The statistical information in a registry record has to be separated into what was planned, what was measured, and what was actually reported. For this study, the record names a continuous primary endpoint and specifies least-squares means and standard errors. It does not report numerical endpoint estimates or a treatment contrast. The design and endpoint descriptions alone are not enough to reproduce the statistical analysis or evaluate its result.
What does a least-squares mean represent?
General: A least-squares mean is a model-based mean. It can summarize an outcome after accounting for terms included in a statistical model, rather than simply averaging all observed values without adjustment. Its interpretation depends on the model, the variables included, and the way the comparison is defined. The registry record does not report the model used for Target P300, so the precise adjustment represented by the stated least-squares mean is not reported in the registry record.
The record lists a standard error as the measure of dispersion accompanying the least-squares mean. General: A standard error describes uncertainty in an estimated mean, rather than the spread of individual measurements. It can help indicate how precisely a mean has been estimated. A standard error by itself does not show the treatment contrast, and without an estimate and a defined comparison it cannot establish the direction or size of a treatment effect.
What would a treatment contrast add?
General: A treatment contrast states the estimated difference between conditions on a defined scale. A confidence interval around that contrast expresses a range of values compatible with the data and the analysis assumptions. Its width conveys precision; it is not a guarantee that the true effect falls within that range. A test result can address compatibility with a specified null hypothesis, but should be interpreted alongside the estimate and interval rather than as a standalone measure of importance.
The registry record does not report a Target P300 contrast, confidence interval, or test result. It therefore does not provide the information needed to describe statistical uncertainty around the treatment comparison. No recalculated comparison is available from the posted summary statistics because the registry record does not report the necessary summary values.
Why does the crossover design matter?
General: In a crossover study, each participant may contribute measurements under more than one treatment condition. A suitable analysis can account for the correlation among measurements from the same participant and can distinguish treatment effects from features such as period or sequence. The design can also be vulnerable to carryover, where an earlier treatment influences measurements in a later period. The analysis should reflect the design and the timing of treatment and measurement.
The registry record identifies a randomized crossover model and gives sequence labels for Day 1 and Day 2 NAC conditions. It does not report the statistical model, any washout interval, whether carryover was assessed, or whether period and sequence terms were included. These details are important to interpreting a crossover estimate, but their absence does not demonstrate that the study did or did not address them in its analysis.
How should the multiple measurements be understood?
The primary outcome is described as daily and measured at Fz, Cz, and Pz. The record also lists Mismatch Negativity intensity, frequency, and duration as secondary outcomes. Multiple electrodes, time points, and outcome measures can generate multiple statistical comparisons. General: When many comparisons are considered, the chance of at least one apparently unusual result can increase if no multiplicity strategy is used. Adjustments or a prespecified hierarchy can help control that issue, but their appropriateness depends on the scientific aims and analysis plan.
The registry record does not report a multiplicity adjustment, hierarchy, or prespecified choice among the Target P300 measurement categories. It notes that the primary outcome was not reduced to one comparison, and it lists 0 analyses. Thus, there is no reported set of outcome estimates with which to evaluate how multiple comparisons were handled.
What do the planning calculations mean?
General: A sample-size illustration estimates the amount of information that might be needed to detect an assumed effect under stated assumptions. It is not an observed result and is not observed power. The registry record describes planning illustrations using a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect expressed as a stated fraction of the observed effect. It specifies that non-time-to-event illustrations are expressed as participants per arm.
These assumptions describe a planning calculation, not the trial’s own design justification or its realized ability to detect an effect. The registry record does not report the trial’s sample-size justification or the full statistical plan. No sample-size illustration should be read as evidence that the study did or did not detect a treatment effect.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 5 outcome measures. It identifies Target P300 as the primary outcome and lists Mismatch Negativity intensity, frequency, and duration as secondary outcomes. The primary endpoint is described as daily and includes measurements from Fz, Cz, and Pz. A registry note says the primary outcome has several categories or time points and was not reduced to one comparison. These features mean that the intended primary comparison is not fully specified in the reported outcome description.
General: Multiple outcomes, electrodes, and time points can lead to multiple statistical comparisons. If many comparisons are made, an apparently notable finding may occur by chance more often than when a single comparison is planned. Statistical plans can address this through a prespecified primary contrast, a hierarchy, or an adjustment for multiplicity. The record does not report whether any of these approaches was used.
The registry record lists 0 analyses and does not give numerical results for the primary or secondary outcomes. It does not report missing-data counts, the reasons for missing measurements, methods for handling missing values, or participant flow into each analysis. Although the primary population is labeled per protocol, the record does not explain the criteria or report how many participants met them. Enrollment of 16 should not be treated as the analyzed population for every endpoint.
The record does not report an intention-to-treat analysis, sensitivity analyses, or a plan for incomplete repeated measurements. These details are not reported in the registry record, so neither the impact of missing data nor the adequacy of any multiplicity approach can be evaluated from it.
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 |
|---|---|---|---|
| Day 1: Placebo NAC; Day 2: Active NAC | 0 | 8 | 0.0% |
| Day 1: Active NAC; Day 2: Placebo NAC | 0 | 8 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Day 1: Placebo NAC; Day 2: Active NAC | 4 of 8 |
| Day 1: Active NAC; Day 2: Placebo NAC | 0 of 8 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Day 1: Placebo NAC; Day 2: Active NAC | Day 1: Active NAC; Day 2: Placebo NAC |
|---|---|---|---|
| Nausea | Gastrointestinal disorders | 4 of 8 | 0 of 8 |
The adverse-event record separates serious adverse events from other adverse events and organizes the counts by treatment sequence. In the group labeled Day 1 placebo NAC; Day 2 active NAC, 8 were listed as at risk for serious events and 0 as affected; 8 were listed as at risk for other adverse events and 4 as affected. In the group labeled Day 1 active NAC; Day 2 placebo NAC, 8 were listed as at risk for serious events and 0 as affected; 8 were listed as at risk for other adverse events and 0 as affected.
These are counts as recorded, not calculated rates. The record does not identify the types of other adverse events, their timing, severity, or relationship to treatment. It also does not explain whether the other-event counts refer to participants or event occurrences, so they should not be interpreted as a count of distinct people. Deaths are not reported in the registry record.
A count of 0 serious events in a group does not establish that an event is impossible or that the treatment is risk-free. The record gives no uncertainty estimates for these safety counts and does not provide enough detail for a comparative safety analysis. The sequence labels also mean these counts should not be read as a simple parallel-group comparison of independent treatment arms.
12. What the Result Does, and Does Not, Mean
The registry record establishes that the study was designed to examine N-acetylcysteine in the context of NMDA antagonism, with cognitive and event-related-potential measurements. It identifies Target P300 as the primary endpoint, describes a randomized, triple-masked crossover design, and reports an enrollment of 16. It does not report the numerical primary outcome results.
That distinction matters. A registered hypothesis and an endpoint description do not tell whether the observed data favored either condition. Without a treatment estimate, its uncertainty, and a defined comparison, the record cannot show the direction or magnitude of a Target P300 difference. It also cannot show whether any difference was estimated precisely or whether it was compatible with a broad range of effects.
The brief summary frames the study as a test of a proposed link between extrasynaptic mechanisms and cognitive effects of NMDA antagonism. The registry record does not report a result that confirms or refutes that proposed mechanism. The secondary outcomes named in the record likewise do not have numerical results reported. Consequently, the scientific hypothesis remains distinct from any evidence of an outcome effect in this record.
The adverse-event counts offer limited descriptive safety information by sequence group. They do not supply a comprehensive account of event types, timing, or causal attribution, and the registry record does not report deaths. These counts should not be treated as a substitute for the missing efficacy estimates or as proof of safety.
General statistical interpretation depends on the estimate, its uncertainty, the analysis population, and the suitability of the analysis for the design. Those pieces are not fully available in the registry record. The appropriate reading is therefore narrow: the record documents the study design and intended measures, but it does not permit a quantitative conclusion about the primary treatment comparison or the proposed mechanism.
13. Why This Trial Matters Statistically
This trial is statistically notable for its crossover structure and its repeated electrophysiological measurements. In a crossover study, a participant can contribute measurements under more than one condition. General: This structure can make within-participant comparisons informative because some characteristics that differ across people remain stable within a person. It also requires analysis that accounts for repeated observations and considers sequence and period effects. The registry record names the design but does not report how these features were modeled.
The endpoint description also illustrates why a measurement label is not the same as a fully defined estimand. Target P300 is measured daily at Fz, Cz, and Pz, and the registry note says the outcome was not reduced to one comparison. A reader needs to know which treatment contrast and measurement summary are being estimated before interpreting a mean or test result. The registry record does not report that numerical comparison.
The trial’s scientific framing connects a proposed mechanism to a measurable ERP response. Statistically, however, an ERP result would support an outcome-level claim only to the extent that the measurement, comparison, and analysis are clearly specified and reported. A result on an electrophysiological measure would not, by itself, establish the proposed mechanism without appropriate supporting evidence.
The record also shows why registry outcomes, analysis populations, and safety summaries should be read separately. It names a per-protocol population, lists multiple outcomes, and provides adverse-event counts, but reports 0 analyses. Without outcome estimates and details of missing data and multiplicity, the design cannot be translated into a reliable quantitative conclusion from the registry record alone.
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 limitation for interpretation is the absence of reported numerical results for Target P300. The record gives the endpoint definition, unit, summary type, dispersion measure, population, and timeframe, but not the treatment-specific estimates, contrast, confidence interval, or test result. It therefore does not allow an assessment of effect size or precision.
The primary outcome is described across daily measurements and three electrode locations, while the registry note says it was not reduced to one comparison. The record does not state which measurement or contrast was the principal inferential target. Multiple secondary outcomes are listed, but their results and any multiplicity procedure are not reported.
The crossover design makes information about treatment sequence, period effects, and possible carryover relevant. The record identifies randomized treatment sequences but does not report a washout interval or the analytical approach to these design features. The arm descriptions are incomplete, limiting the available detail about procedures. The record does not report the full protocol, randomization method, masking roles, or statistical plan.
The primary population is listed as per protocol, but the criteria, analyzed count, exclusions, and participant flow are not reported. Missing outcome data and their handling are also not reported. The stated enrollment of 16 cannot be assumed to equal the number contributing data to each analysis.
The condition field lists cognitive dysfunction, whereas the brief summary describes healthy humans. The record does not explain the difference. Finally, adverse-event counts lack event descriptions, timing, attribution, and uncertainty estimates; deaths are not reported in the registry record. These limitations are specific to what the registry record documents and do not establish what may appear in other study materials.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: N-acetylcysteine and NMDA Antagonist Interactions — NCT00611897.
- Registry record last updated 2015-05-08; status last verified 2015-05.
- Results first posted 2015-05-08.
- 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
NCT00611897, titled N-acetylcysteine and NMDA Antagonist Interactions, is recorded as a completed randomized, triple-masked crossover study in Phase 1 and Phase 2. Enrollment was 16. The brief summary describes a study of cognitive effects of NMDA antagonism in healthy humans; the condition field lists cognitive dysfunction.
The registered comparison is N-acetylcysteine and ketamine versus placebo and ketamine. Target P300, measured daily in microvolts at Fz, Cz, and Pz, is the primary outcome. Mismatch Negativity intensity, frequency, and duration are listed as secondary outcomes. The primary population is per protocol, and the stated summaries are least-squares means with standard errors.
The registry record lists 0 analyses and does not report numerical primary or secondary outcome results. It reports 0 serious adverse events in each sequence group, with other adverse-event counts of 4 and 0, respectively. Deaths are not reported in the registry record. The available record supports describing the design and endpoints, but not quantifying the primary treatment comparison.