Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (NCT04711005), a randomized phase 1 study. The primary outcome is Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of (2R,6R)-Hydroxynorketamine.

2. Clinical Question

3. Trial Design

NCT04711005 is a completed Phase 1 study sponsored by the National Institute of Mental Health (NIMH). The registry describes it as randomized, double-blind, and sequential, with enrollment of 74. The study start is listed as 2021-01-11 and primary completion as 2023-04-30. Its official title describes a placebo-controlled single ascending dose (SAD), multiple ascending dose (MAD), and CSF capture study of safety, pharmacokinetics, and pharmacodynamics.

The SAD portion is described as six cohorts receiving a single slow-infusion intravenous dose. The dose levels listed are 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, and 4.0 mg/kg. Each SAD cohort has 6 participants in the posted primary outcome results. Safety, pharmacokinetics, and qEEG monitoring are described for the dose levels.

The MAD portion is described as two cohorts receiving repeated infusions. There is a schedule discrepancy within the registry record: the study summary says doses are administered on days 1, 4, 8, and 11, while the arm descriptions say days 1, 4, 7, and 10. The record does not explain this difference. It also describes a separate CSF capture cohort receiving a single dose, with pharmacokinetic samples collected from blood and cerebrospinal fluid.

Placebo is described as sterile saline administered by slow intravenous infusion. Although the overall study is described as randomized and double-blind, the registry record does not report the allocation procedure or the specific randomization and masking arrangements within each cohort. The primary safety endpoint excludes the CSF cohorts.

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.

Only the first 6 of 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Does not include the CSF cohorts as those were exploratory.

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.

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Adverse Events as a Measure of Safety and Tolerability of (2R,6R)-Hydroxynorketamine, measured over 8 days post dosing (SAD).

The primary endpoint is the number of participants with adverse events as a measure of safety and tolerability of (2R,6R)-Hydroxynorketamine. The registry describes the events of interest as investigational-product-related adverse events and serious adverse events, with a timeframe of 8 days post dosing for the SAD portion. It specifies that the primary population does not include the CSF cohorts because they were exploratory.

A participant count is a direct way to describe how many people in a cohort experienced the event category being tracked. It is a binary outcome at the participant level: a participant either is or is not counted as having the event for the endpoint. General statistical context: such counts can help characterize observed safety experience, but their interpretation depends on the event definition, follow-up period, cohort size, and completeness of event reporting. Counts alone do not show how uncertain a rate is, nor do they establish whether groups differ.

The posted primary outcome results list counts for the SAD cohorts. They do not provide an accompanying confidence interval, inferential test, or placebo comparison for this endpoint. The registry record does not report further endpoint adjudication or the precise rules used to attribute events to the investigational product.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are described only to the extent that the registry record reports them. It identifies the study as randomized, double-blind, and sequential, and posts a participant-count endpoint. It does not report a statistical analysis plan or inferential results for the primary endpoint. General explanations below describe how such methods are commonly interpreted; they do not establish which procedures were used in this trial.

What does a participant count represent?

The primary outcome is a count of participants with qualifying adverse events, rather than a continuous measurement such as a laboratory value. The endpoint is therefore naturally interpreted as a participant-level binary outcome: each participant is either counted as having a qualifying event or is not. The posted SAD values give the number counted in each cohort. The registry also gives the cohort size, allowing the reader to see the scale of the group being described, but it does not post a modeled estimate of event probability or a confidence interval.

General statistical context: a count is useful for describing what occurred in a defined group, while an estimate with an interval can communicate uncertainty about an underlying event frequency. With small groups, an interval may be wide. The registry does not report intervals for the primary outcome, and no additional precision measure should be inferred from the point counts alone.

What does randomization contribute?

Randomization is listed as a design feature, and double masking is also listed. In general, random allocation can reduce systematic differences between groups, while masking can reduce some forms of behavior or assessment influenced by knowledge of assignment. Those design features do not by themselves demonstrate that a particular analysis was performed or that a posted result is a valid treatment comparison. For the primary endpoint, the record lists SAD cohort results but no placebo result in the endpoint arms and no treatment-versus-placebo estimate. The registry record does not report allocation details, whether the SAD cohorts were randomized against placebo within each dose level, or how masking was maintained.

Why is a direct comparison unavailable?

A two-arm comparison requires outcome information for both arms in the comparison and a defined analysis. The registry indicates that values are missing or not estimable for a two-arm comparison of this binary endpoint. It posts no analyses. Accordingly, there is no reported difference, ratio, confidence interval, or significance test for the primary safety endpoint. This is a limit on what can be concluded from the posted results, not evidence that the groups had identical outcomes.

How should planning calculations be read?

The planning approach described for the sample-size illustrations uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes planning for a stated fraction of the observed effect. The endpoint's values are not available or estimable for a two-arm comparison, so the record indicates that the relevant calculation is skipped. These illustrations are planning exercises, not observed power and not the trial's own design justification. The registry record does not report the trial's sample-size justification, target power, or the assumptions used when the study was designed.

What role does over-dispersion have?

General statistical context: over-dispersion matters when count data vary more than a chosen statistical model expects. A model that ignores excess variation can give uncertainty estimates that are too narrow. It is not possible to assess over-dispersion from the posted primary endpoint as described: the endpoint is a participant count in small cohorts, and the registry reports no fitted count model, dispersion estimate, or model-based uncertainty. No claim about over-dispersion or a count regression method is warranted from the record.

What can a confidence interval add?

General statistical context: a confidence interval expresses the uncertainty associated with an estimate under specified assumptions and a specified method. It is not a guarantee that the true value lies within the interval, and its interpretation depends on the analysis design. No confidence interval for the primary endpoint is reported in the registry record. The absence of an interval means the posted counts should be read descriptively rather than as precise estimates of event frequency.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("SAD Cohort 1", "SAD Cohort 2", "SAD Cohort 3", "SAD Cohort 4", "SAD Cohort 5", "SAD Cohort 6")
n      <- c(6, 6, 6, 6, 6, 6)
events <- c(1, 0, 1, 1, 1, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  SAD Cohort 1  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SAD Cohort 2  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  SAD Cohort 3  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SAD Cohort 4  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SAD Cohort 5  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SAD Cohort 6  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 6 outcome measures but posts no secondary outcomes and no analyses. It does not report how many statistical hypotheses were planned, whether any multiplicity adjustment was specified, or whether there were prespecified primary comparisons beyond the stated endpoint. The statistical analysis plan is not reported in the registry record.

General statistical context: multiplicity arises when several outcomes, time points, or comparisons are examined. Without an approach to control or describe the resulting uncertainty, a nominal test result can be harder to interpret as confirmatory. Here, there are no posted inferential tests for the primary endpoint and no posted secondary results, so the record does not allow assessment of multiplicity handling or selective reporting across analyses.

The registry does not report missing-data methods, the amount of missing outcome information, imputation procedures, or sensitivity analyses. The primary outcome population is described as excluding CSF cohorts because they were exploratory. Beyond that exclusion, the analysis population and the handling of withdrawals or incomplete follow-up are not reported in the registry record. The SAD endpoint timeframe is given as 8 days post dosing, but the record does not describe how participants without complete observation over that period were handled.

These omissions limit interpretation of the posted counts: they do not establish whether every enrolled participant contributed complete endpoint information under a prespecified analysis rule. The record also does not report whether analyses were conducted according to assigned treatment or according to treatment received. No inference about those analysis choices can be made from the cohort counts alone.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The serious adverse event listing reports zero related serious adverse events for each group shown: the six SAD cohorts, two MAD cohorts, placebo, and the CSF capture cohort. It also reports zero deaths in each of those groups. These entries concern the registry's listed related serious-event category; they should not be restated as proof that no serious event of any kind occurred, because the posted fields distinguish related events from other adverse events.

The listing gives 6 participants at risk in each SAD cohort, 6 in MAD Cohort 1, 9 in MAD Cohort 2, 19 in the placebo group, and 4 in the CSF capture cohort. Counts for other adverse events are also listed by group: SAD Cohort 1 has 1, SAD Cohort 2 has 0, SAD Cohort 3 has 1, SAD Cohort 4 has 1, SAD Cohort 5 has 1, SAD Cohort 6 has 2, MAD Cohort 1 has 1, MAD Cohort 2 has 2, placebo has 5, and the CSF capture cohort has 4. These figures should be read as the listed category counts, not as a randomized comparison or as the primary endpoint result.

The registry record does not post a statistical comparison for serious adverse events, describe adjudication procedures, or provide further detail about event severity or timing. Zero recorded related serious events in these groups is a descriptive observation within this study and does not establish the absence of risk in other participants or settings.

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

The results mean that the registry recorded the stated number of participants meeting the primary safety endpoint in each SAD cohort during the specified follow-up. They also show that the adverse-event listing reports zero related serious adverse events and zero deaths in each listed group. These are descriptive findings from a Phase 1 study of healthy volunteers, with small cohorts and a primary endpoint focused on safety and tolerability.

The results do not provide a randomized comparison of the investigational product with placebo for the primary endpoint. They do not quantify an adjusted treatment effect, its uncertainty, or a dose-related trend. The record posts no analyses, no primary endpoint confidence interval, and no secondary outcome results. Counts alone cannot establish whether apparent differences among cohorts reflect treatment, chance, differences in event ascertainment, or other factors.

The study title and summary describe pharmacokinetic and pharmacodynamic aims, including qEEG monitoring and a CSF capture component. However, the primary results are safety counts; the registry record does not post corresponding pharmacokinetic or pharmacodynamic analyses in its listed results. These safety findings therefore do not answer questions about clinical benefit or effectiveness for Major Depressive Disorder. Although that condition is listed in the registry, the study summary describes healthy volunteers, and the primary endpoint is not an efficacy outcome in patients.

General statistical context: early-phase studies can describe initial safety observations and characterize what was measured under the study conditions. They are not automatically informative about uncommon events or about safety in populations unlike those enrolled. The sample sizes and follow-up recorded constrain how broadly the counts can be generalized. The record does not report a sample-size justification or analysis plan that would support a broader inferential claim.

14. Why This Trial Matters Statistically

This study is statistically instructive because it combines a sequential dose-escalation design with a binary safety endpoint and several distinct study components. The SAD cohorts provide descriptive counts at multiple dose levels, while the registry separately describes repeated dosing and CSF capture. Keeping those components distinct matters: the primary endpoint explicitly excludes the CSF cohorts, and the posted primary values are not a single pooled treatment-versus-control estimate.

The record also illustrates the difference between an overall design label and a reported analysis. The study is described as randomized and double-blind, but the posted primary outcome results do not include a placebo value or a two-arm estimate. Randomization can be important to comparative inference in general, but a comparative conclusion requires reported outcome data and an analysis that matches the comparison of interest. Those elements are not reported for this endpoint.

Small cohort counts invite careful interpretation. A count conveys exactly how many participants were recorded in the endpoint category, but without an uncertainty interval or prespecified comparative analysis it should not be treated as a precise estimate of risk. The absence of posted secondary outcomes and analyses also limits the ability to assess how safety findings relate to the other stated study aims.

Finally, the different MAD dosing schedules in the study summary and arm descriptions show why registry entries should be read critically. The record does not explain the discrepancy. Recognizing unresolved reporting details, rather than silently choosing one version, is part of sound statistical interpretation.

15. 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 safety result is reported as counts for SAD cohorts with 6 participants in each cohort. Those limited group sizes mean the counts offer only a narrow description of the observed study experience. The registry record does not provide confidence intervals, hypothesis tests, or an analysis comparing the dose cohorts. It also does not post a placebo value for the primary endpoint, despite listing placebo as an intervention and describing the overall study as placebo-controlled.

The endpoint definition refers to investigational-product-related adverse events and serious adverse events, but the record does not report the detailed attribution process, event coding rules, or adjudication procedures. The separate adverse-event listing includes additional groups and categories, which should not be substituted for the primary endpoint. The follow-up period is stated for the SAD endpoint, but completeness of follow-up and handling of missing observations are not reported.

The study summary and arm descriptions give different MAD dosing schedules: days 1, 4, 8, and 11 in the summary, compared with days 1, 4, 7, and 10 in the arm descriptions. The registry record does not resolve this discrepancy. The primary endpoint excludes the CSF cohorts, and no secondary results or analyses are posted, limiting interpretation of the other study aims.

Additional limitations include the absence of a reported statistical analysis plan, sample-size justification, analysis population definition beyond the stated CSF exclusion, and missing-data procedures. The posted safety counts do not address efficacy, and the registry record does not report pharmacokinetic or pharmacodynamic analyses alongside these primary results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine — NCT04711005.
• Registry record last updated 2024-06-06; status last verified 2023-02.
• Results first posted 2024-06-06.
• 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.

19. Record Summary

NCT04711005 is a completed Phase 1 randomized, double-blind, sequential study sponsored by the National Institute of Mental Health (NIMH), with enrollment of 74. The study summary describes healthy volunteers and includes SAD, MAD, and CSF capture components. The primary endpoint counts participants with investigational-product-related adverse events and serious adverse events during 8 days post dosing in the SAD cohorts; it excludes the CSF cohorts.

The posted SAD endpoint counts are 1, 0, 1, 1, 1, and 2 across the six cohorts, each of which lists 6 participants. The adverse-event listing reports zero related serious adverse events and zero deaths in each group. No two-arm primary endpoint analysis, secondary outcome results, or statistical analyses are posted. The record does not report the statistical analysis plan, missing-data methods, or sample-size justification. A difference in the stated MAD dosing schedule remains unexplained in the registry record.