A Study of CLE-100 (Oral Esketamine) as an Adjunctive Treatment to Standard Antidepressants for Major Depressive Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of CLE-100 (Oral Esketamine) as an Adjunctive Treatment to Standard Antidepressants for Major Depressive Disorder (NCT06340958), a randomized phase 2 study. The primary outcome is Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Score.

2. Clinical Question

This is an adjunctive-treatment question: participants continued standard antidepressant treatment while receiving CLE-100 or placebo. The comparison therefore concerns the added study tablet under the trial conditions, rather than CLE-100 used alone or a comparison between different background antidepressants. The registry record describes a parallel-group study, so participants were assigned to one of the two groups rather than crossing between them.

The clinical question is framed around change in a clinician-rated symptom scale, not remission, long-term outcomes, or a direct measure of functioning. The registry lists additional outcomes, including change in Clinical Global Impression-Severity, change in MADRS score, and safety and tolerability. The information reported for the primary endpoint is the change in MADRS at 29 days. Longer-term efficacy outcomes and the criteria used to define an inadequate response are not reported in the registry record.

3. Trial Design

This was a Phase 2, randomized, double-blind, placebo-controlled, multicenter, parallel-design study. The registry reports 99 participants enrolled and a completed status. The study start date is 2024-03-18, and the primary completion date is 2025-06-06. The sponsor is Clexio Biosciences Ltd.

Participants with major depressive disorder and an inadequate response to standard antidepressants were assigned to CLE-100 or placebo. Both groups continued their current antidepressant drug. The CLE-100 group received 1 oral tablet once daily for 4 weeks; the placebo group received 1 oral tablet once daily for 4 weeks. The double-blind design means the registry identifies masking of participants and study personnel, but further details about who was masked and how masking was maintained are not reported in the registry record.

The primary endpoint was change from baseline in MADRS score at 29 days. The primary population was the Double-Blind Efficacy Analysis Set, described as a subset of the Intention to Treat population. The registry reports 50 participants in the CLE-100 group and 49 in the placebo group for the posted endpoint summaries. Those group counts sum to the enrollment total, but the registry does not provide a participant-flow account explaining exclusions, withdrawals, or the exact analysis-set membership beyond its brief description.

The reported primary comparison used a Mixed Models Repeated Measures analysis and gave a least-squares mean difference between groups. The registry lists 4 outcome measures and 1 analysis. It also identifies secondary outcomes involving Clinical Global Impression-Severity, MADRS, and safety and tolerability. The detailed protocol, eligibility criteria, randomization procedure, allocation concealment, visit schedule, and full statistical analysis plan are not reported in the registry record. Nor is the original sample-size justification reported, so the enrollment number cannot be interpreted as evidence that a particular power target was planned.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Double-Blind Efficacy (DBE) Analysis Set, a subset of the Intention to treat (ITT) population

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Score, measured over 29 days.

The primary endpoint is change from baseline in the Montgomery-Asberg Depression Rating Scale score at 29 days. MADRS is a clinician-administered measure of depression severity commonly used in depression trials to select participants and assess outcomes. Its 10 items are scored from 0, meaning an item is absent or normal, to 6, meaning symptoms are severe or continuously present. The total possible score is 60, and higher scores represent a more severe condition.

Change from baseline describes how a participant’s score differs from the starting measurement. A negative change indicates a reduction in score; because higher MADRS scores represent greater severity, a more negative group mean change corresponds to a larger average score reduction. This is a continuous outcome: its values can vary across a range rather than being limited to categories such as improved or not improved.

The registry reports least-squares means for the two groups, with standard errors of 1.5 for CLE-100 and 1.55 for placebo. The reported mean changes are -11.66 and -8.7, respectively. The sponsor’s mixed-model comparison is a least-squares mean difference of -2.96. A group average does not describe every participant’s experience, and the registry does not report the distribution of individual changes or a threshold for a clinically meaningful change. The endpoint therefore addresses average symptom-scale change by 29 days; it does not, by itself, establish remission, persistence of change, or outcomes beyond that assessment time.

7. Results Posted in the Registry

• CLE-100: mean -11.66 versus -8.70 on control; difference -2.96 (95% CI -7.19 to 1.27), standardized effect d = -0.28; z-test p = 0.170.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous primary outcome: change from baseline in MADRS score. For a continuous endpoint, a mean summarizes the average observed change in a group. The CLE-100 group’s reported mean change is -11.66, and the placebo group’s is -8.7. The corresponding standard errors are 1.5 and 1.55. A standard error describes the uncertainty in an estimated mean, rather than the spread of individual participant outcomes. Individual-level variability is not directly reported for this endpoint.

What does a mean difference represent?

The mean difference compares the average outcome between groups. The reported comparison is CLE-100 minus placebo, with an estimated difference of -2.96. Because a decrease in MADRS score indicates a reduction in measured severity, a negative difference points toward a larger average reduction in the CLE-100 group. It is a contrast between group averages and does not imply that all participants had changes of that size or direction.

The primary reported model is Mixed Models Repeated Measures, abbreviated MMRM, and the parameter is a least-squares mean difference. In general, a least-squares mean is a model-based estimate of a group mean, often adjusted for variables or repeated observations included in the model. Repeated-measures models can use outcome measurements collected at multiple times and account for how measurements from the same participant are related. The registry does not report the model’s covariates, covariance structure, repeated time points used, or missing-data assumptions. The precise model specification therefore cannot be reconstructed from the registry record.

Why are standard errors and confidence intervals useful?

A confidence interval expresses uncertainty around an estimated effect under the assumptions of the analysis. The sponsor-reported difference is -2.96, with a 95% confidence interval from -7.01 to 1.09. The interval includes zero, meaning the reported data do not rule out no average difference under that analysis. Its width also indicates that effects in either direction remain compatible with the estimate. A confidence interval is not a range containing a fixed proportion of individual participants’ outcomes, and it is not a guarantee that the true effect lies inside it.

The sponsor reports p = 0.15 for its MMRM analysis. In general, a p-value describes how incompatible the observed data, or more extreme data, are with a specified null model, assuming the analysis assumptions hold. It does not measure the size or importance of an effect, and it is not the probability that the null hypothesis is correct. The registry record does not describe a multiplicity adjustment or a broader prespecified testing hierarchy, so the p-value should be read as the reported result for this comparison, not as evidence that all possible sources of uncertainty have been addressed.

What is the recalculation?

The unadjusted recalculation uses the posted group means and standard errors to derive a simple comparison. The approximate pooled standard deviation is 10.73, and the standardized difference is -0.276. The recalculated mean difference is -2.96, with a 95% confidence interval from -7.188 to 1.268 and p = 0.17. This calculation treats the group summaries as the basis for an unadjusted comparison; it does not reproduce the sponsor’s MMRM. The pooled standard deviation is approximate because it is derived from the reported standard errors. The recalculation is useful as a transparent reference, while the sponsor’s model remains the analysis reported by the registry.

General statistical context: repeated measurements can provide more information than a single measurement, but the model’s assumptions and handling of incomplete observations matter. General statistical context: over-dispersion is a concern when data vary more than a model’s assumed distribution allows; it can make standard errors too small if not accommodated. The primary endpoint is continuous and the registry identifies an MMRM, but it does not report an over-dispersion assessment or a model diagnostic procedure.

What does the analysis population mean?

The primary endpoint population is described as the Double-Blind Efficacy Analysis Set, a subset of the ITT population. In general, an intention-to-treat analysis aims to retain participants in their assigned groups, while a subset analysis may apply additional eligibility or data requirements. The registry does not define those requirements, give the subset size, or describe the participant flow into the analysis set. This limits assessment of whether the analysis population preserves the randomized comparison and how exclusions may affect interpretation.

Randomization and double-blinding are design features intended, in general, to reduce systematic differences and expectations that could influence comparisons. The record states that the trial was randomized and double-blind, but details of sequence generation, concealment, masking checks, and protocol adherence are not reported in the registry record. These features support the intended comparison, while the unavailable details limit a fuller evaluation of implementation.

10. Confidence Intervals and Precision

The sponsor-reported estimate is a least-squares mean difference of -2.96 MADRS units, with a 95% confidence interval from -7.01 to 1.09. The interval crosses zero and includes both negative and positive values. The point estimate favors a larger mean reduction in the CLE-100 group based on the direction of the scale, but the interval indicates that the data do not pin down the direction or magnitude with high precision. Values near zero and differences on either side remain compatible with the reported interval under the model.

In general, a confidence interval shows the range of estimates that are reasonably compatible with the data and the assumptions used to calculate it. It is not a range for individual participant responses and does not assign a probability to the true effect after the study. Its interpretation depends on the statistical model and its assumptions. The MMRM model details and missing-data assumptions are not reported in the registry record, which makes independent evaluation of the interval’s construction incomplete.

The unadjusted recalculation gives a 95% confidence interval from -7.188 to 1.268. Its endpoints differ from the sponsor’s interval because the calculation is based on posted group summaries and an approximate pooled standard deviation, rather than the sponsor’s repeated-measures model. Both intervals include zero. The sponsor’s own analysis remains the principal reported estimate; the recalculation offers a simple comparison, not a substitute model.

The standard errors for the group means are 1.5 for CLE-100 and 1.55 for placebo. Standard errors quantify precision of estimated means, not the range of scores among participants. The registry does not report a threshold for a clinically meaningful MADRS difference, so statistical precision cannot by itself establish whether a particular effect would be important to patients or clinicians. The confidence interval is most useful as a reminder that the point estimate should not be read in isolation.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for this continuous-outcome comparison, not total events. The planning illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. The registry record does not report the assumptions used for the trial’s original design or its original sample-size justification; these figures are planning illustrations based on the observed result, not a reconstruction of the trial’s intended design.

For each effect scenario, the 80% power column gives the number of participants per arm that the illustration estimates would be needed for an 80% chance of detecting an effect of that size under the stated assumptions, if the effect were real and the model assumptions held. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning concepts: power is the probability of a statistically significant result under a specified effect and assumptions, not the probability that a study conclusion is correct.

The listed scenarios are planning for 100% of the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect. The illustration gives 207 participants per arm and 277 participants per arm for 80% and 90% power, respectively, when planning for 100% of the observed effect. For 75% of the observed effect, the figures are 367 and 491 participants per arm. For 50% of the observed effect, they are 825 and 1,105 participants per arm. Smaller effects need more participants to detect, all else equal, which is why the required sample sizes rise as the assumed fraction of the observed effect gets smaller.

This is not observed power. It does not describe the chance that the completed trial had of detecting its actual effect, and it does not turn the observed result into evidence of a particular probability of success. The observed estimate is uncertain, and planning directly from it may produce an unstable illustration. The calculations are most appropriately read as conditional sample-size scenarios under the stated assumptions.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -2.960; pooled standard deviation σ = 10.728.
2. n = 2 × (1.96 + 0.842)² × 10.728² / -2.960² = 206.2, rounded up to 207 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -2.96                      # observed difference in means
sigma <- 10.7277364759257                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(6340958)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 207 (80% power), 277 (90% power)
 75% of observed effect: n per arm = 367 (80% power), 491 (90% power)
 50% of observed effect: n per arm = 825 (80% power), 1,105 (90% power)
power.t.test: 207.2 
Simulated power at n = 207 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The sponsor-reported primary analysis uses Mixed Models Repeated Measures and reports a least-squares mean difference of -2.96, with a 95% confidence interval from -7.01 to 1.09 and p = 0.15. This is the registry’s own analysis and should be distinguished from a simple recalculation based on group summary statistics.

The recalculation gives the same point estimate, -2.96, but a 95% confidence interval from -7.188 to 1.268 and p = 0.17. It is unadjusted and uses the reported group means and standard errors, including an approximate pooled standard deviation. It does not reproduce the repeated-measures model or any adjustments that may have been made in the sponsor’s analysis. A difference in interval width or p-value can arise because the analyses use different statistical information and assumptions.

Neither analysis yields a confidence interval excluding zero. The estimates therefore both convey uncertainty about the direction and magnitude of the group difference. The recalculation is a check on the posted summaries, not a competing primary analysis. The detailed MMRM specification is not reported in the registry record, so the reasons for the precise difference between the two intervals cannot be fully assessed from the available information.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures and 1 analysis. It describes secondary outcomes involving change from baseline in Clinical Global Impression-Severity, change from baseline in MADRS score, and safety and tolerability. The primary endpoint is change from baseline in MADRS at 29 days. The record does not describe a multiplicity adjustment, a hierarchy of endpoints, or how the type I error rate was controlled across outcomes or analyses. It is therefore not reported in the registry record whether the primary comparison was part of a larger testing strategy or whether secondary comparisons were intended to support formal confirmatory claims.

In general, multiplicity arises when several hypotheses are tested. Testing multiple outcomes or time points can increase the chance of at least one apparently notable result by chance unless the analysis plan accounts for the testing structure. The registry’s count of outcome measures and analyses does not, by itself, establish how many hypothesis tests were conducted or whether an adjustment was applied. The detailed prespecified statistical analysis plan is not reported in the registry record.

The primary analysis population is identified as the Double-Blind Efficacy Analysis Set, a subset of the ITT population. The registry does not report the number of participants in that set, the rules used to define it, or the number of participants with endpoint data at each assessment. It does not report missing-data counts, reasons for missingness, or the method used to handle missing MADRS measurements. Although MMRM is named as the analysis method, its missing-data assumptions and sensitivity analyses are not reported in the registry record.

In general, missing-data methods matter because the result can be affected if participants with unobserved outcomes differ systematically from those with observed measurements. Repeated-measures models can accommodate incomplete measurement patterns under assumptions, but the specific assumptions and diagnostic or sensitivity checks cannot be evaluated without the model details. The registry also does not report interim analyses, stopping rules, protocol deviations, or sensitivity analyses. These omissions limit a complete assessment of how robust the primary result is to analysis choices and incomplete follow-up.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: transaminases increased (2.0%).

The registry reports serious adverse events in 1 of 50 participants at risk in the CLE-100 group and 0 of 49 participants at risk in the placebo group. It reports no deaths in either group. These are counts of participants with serious adverse events, not counts of all adverse-event episodes. The registry also lists “Transaminases increased” among the top serious terms, with 2.0%; it does not provide a group attribution for that term in the information reported.

The counts are descriptive. With the available registry information, they do not establish whether a difference between groups is reliable, nor do they determine the cause of an event. The record does not report the event narratives, seriousness criteria, timing, relatedness assessment, or the complete list of serious-event terms by group. These details are not reported in the registry record.

The record separately reports other adverse events affecting 20 of 50 participants at risk in the CLE-100 group and 4 of 49 in the placebo group. These are not the serious-event counts and should not be conflated with them. The posted information does not give enough detail to assess event duration, severity, recurrence, or how events affected treatment continuation. Safety and tolerability were listed as an outcome, but the available summaries provide limited context for interpreting the observed counts.

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

The registry reports reductions in mean MADRS score in both groups by 29 days: -11.66 for CLE-100 and -8.7 for placebo. The sponsor-reported difference is -2.96 in the direction of a larger average score reduction with CLE-100. The 95% confidence interval, from -7.01 to 1.09, includes zero, and the reported p-value is 0.15. These results describe an uncertain comparison, not a definitive finding that the groups differed or were equivalent.

A non-significant p-value does not show that treatments are the same. It indicates that the reported analysis did not provide sufficiently strong evidence against its null model under the analysis used. At the same time, a point estimate in one direction does not establish a reliable difference. The confidence interval conveys that a range of values, including zero, is compatible with the reported result. The registry does not report a threshold for a clinically meaningful change, so the size of the estimate cannot be classified against such a threshold from this record.

The findings concern one outcome, a specific assessment at 29 days, and an adjunctive-treatment context in participants described as having an inadequate response to standard antidepressants. They do not address longer-term outcomes, CLE-100 as a standalone treatment, other doses, or participants outside the described population. The primary analysis used a defined efficacy subset, and details about missing data and model assumptions are not reported in the registry record.

The safety summaries report 1 participant with a serious adverse event in the CLE-100 group and none in the placebo group, with no deaths in either group. These counts are useful descriptions of what was recorded, but the registry information is not sufficient to establish causality or compare safety reliably. Overall, the posted results should be read as estimates with substantial uncertainty and limited duration, rather than as a complete account of efficacy or safety.

17. Why This Trial Matters Statistically

This study illustrates why a trial result should be read through both its point estimate and its uncertainty. The mean change favored a greater reduction in MADRS score in the CLE-100 group, but the sponsor-reported confidence interval includes zero. Reporting the estimate alone would omit how broadly the data remain compatible with different group differences.

The comparison also distinguishes a model-based primary analysis from a simple summary-statistic recalculation. The sponsor’s MMRM result and the recalculation have the same point estimate, but their intervals and p-values differ. That distinction matters because an unadjusted calculation based on group summaries does not reproduce a repeated-measures analysis. Clear separation of the reported model result and a recalculation helps readers understand what each number can support.

The registry identifies a specific efficacy subset and a 29-day endpoint, while leaving important details about model specification, missing data, multiplicity, and the original sample-size rationale unreported. Those gaps do not erase the posted findings, but they limit independent evaluation of robustness and design intent. Similarly, the planning illustrations are conditional scenarios based on the observed effect, not evidence that the completed trial was adequately powered.

For clinical researchers and statisticians, the central lesson is to connect the scale’s direction, the comparison estimate, its confidence interval, the analysis population, and the study duration. Doing so avoids interpreting a p-value in isolation or treating a group mean as an individual outcome. The record offers a focused example of how inferential uncertainty and incomplete methodological detail shape interpretation of a Phase 2 trial.

18. 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 provides limited detail about eligibility and participant flow. It describes an inadequate response to standard antidepressants and an objective involving inadequate response to at least 2 antidepressants, but the operational definition and supporting criteria are not reported. The number assigned, treated, completing follow-up, and included in the Double-Blind Efficacy Analysis Set is not separately described, beyond the endpoint group counts of 50 and 49.

The primary analysis population is a subset of the ITT population, but the criteria defining that subset are not reported. This makes it difficult to judge how the analyzed groups relate to all randomized participants. The record names an MMRM but does not report covariates, covariance structure, repeated measurements included, missing-data assumptions, or sensitivity analyses. Independent reproduction of the sponsor’s model is therefore not possible from the registry summary.

The endpoint is reported at 29 days, following 4 weeks of daily dosing. Longer-term outcomes and durability are not reported. A clinically meaningful MADRS threshold is also not reported, so the clinical importance of the estimated difference cannot be determined from the posted summary alone. The record lists other outcomes but gives limited results for those outcomes in the information available.

Multiplicity procedures, interim analyses, stopping rules, and the trial’s original sample-size justification are not reported in the registry record. The sample-size illustrations use the observed effect and stated assumptions, which are not the same as the original planning rationale. Safety summaries provide counts but not detailed event narratives, timing, relatedness, or complete group-specific serious-event terms. These limitations call for cautious interpretation of both efficacy and safety summaries.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of CLE-100 (Oral Esketamine) as an Adjunctive Treatment to Standard Antidepressants for Major Depressive Disorder — NCT06340958.
• Registry record last updated 2026-06-23; status last verified 2026-05.
• Results first posted 2026-06-23.
• 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.

22. Record Summary

NCT06340958 is a completed Phase 2, randomized, double-blind, placebo-controlled, multicenter, parallel-design study sponsored by Clexio Biosciences Ltd. It enrolled 99 participants with major depressive disorder and an inadequate response to standard antidepressants. CLE-100 or placebo was added to participants’ current antidepressant drug as 1 oral tablet once daily for 4 weeks.

The primary endpoint was change from baseline in MADRS score at 29 days. The sponsor-reported MMRM least-squares mean difference was -2.96, with a 95% confidence interval from -7.01 to 1.09 and p = 0.15. The recalculated unadjusted comparison also estimated -2.96, with a 95% confidence interval from -7.188 to 1.268 and p = 0.17. Both intervals include zero.

The record reports 1 participant with a serious adverse event in the CLE-100 group and 0 in the placebo group, with no deaths in either group. Further details on the original design assumptions, missing data, model specification, multiplicity, and participant flow are not reported in the registry record.