Study to Evaluate TNX-601 ER Monotherapy Versus Placebo in Patients With Major Depressive Disorder (MDD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate TNX-601 ER Monotherapy Versus Placebo in Patients With Major Depressive Disorder (MDD) (NCT05686408), a randomized phase 2 study. The primary outcome is Montgomery Asberg Depression Rating Scale (MADRS).

2. Clinical Question

3. Trial Design

The registry record describes a Phase 2, randomized, placebo-controlled, parallel-group study of TNX-601 ER monotherapy in patients with MDD. Enrollment was 132. The study is marked completed. Its recorded start date is 2023-03-02 and its primary completion date is 2023-09-29.

Participants were assigned to TNX-601 ER, 39.4 mg, or placebo. Both were taken orally once daily for 6 weeks. The study title describes the design as double-blind, while the registry masking field records quadruple masking. These are the descriptions appearing in separate registry fields; additional information about who was masked or how masking was maintained is not reported in the registry record.

The primary outcome was change from baseline, identified as Visit 2, in MADRS total score at Week 6. Results are reported for the ITT population, which the record defines as all randomized patients who received at least one dose of investigational product. The posted group summaries include 68.0 participants for placebo and 64.0 for TNX-601 ER. The record also lists Clinical Global Impression of Severity (CGI-S) and Sheehan Disability Scale (SDS) as secondary outcomes, both assessed over the Day 1 and Week 6 timeframe.

The record does not report the original sample-size justification, the detailed randomization procedure, or further protocol details. The design features should therefore be read as the registry's recorded information, rather than as a complete account of the protocol.

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

Analysis population for the primary outcome, as defined in the registry: Results reported for ITT population, which includes all randomized patients who received at least one dose of IP.

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 Montgomery Asberg Depression Rating Scale (MADRS), measured over Day 1 and Week 6.

The primary endpoint is change from baseline in the MADRS total score at Week 6. MADRS is a continuous measure of depressive symptoms, with scores from 0 to 60; lower scores indicate less depression. Because the endpoint is a change score, negative values in the posted summaries indicate a decrease in score relative to baseline. The registry reports least-squares mean changes, rather than raw group averages, and gives standard errors for those estimates.

General: A continuous symptom scale can retain information across its range, rather than reducing participants to a limited set of categories. Comparing change from baseline can describe how scores shifted during the study, while the between-group comparison addresses whether those shifts differed between randomized groups. A scale's numerical direction matters: for MADRS, a lower score indicates less depression, so a negative change corresponds to a decrease in measured symptoms.

The registry record identifies the primary endpoint and its timeframe but does not describe the clinical threshold, if any, that would constitute a meaningful difference for patients. It also does not report how the least-squares means were modeled or adjusted. The endpoint therefore supports interpretation of the posted score changes and their estimated between-group difference, but not conclusions about unreported clinical thresholds or analysis procedures.

7. Results Posted in the Registry

• TNX-601 ER, 39.4 mg: mean -12.70 versus -12.80 on control; difference 0.10 (95% CI -3.53 to 3.73), standardized effect d = 0.01; z-test p = 0.957.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Clinical Global Impression of Severity (CGI-S)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • TNX-601 ER, 39.4 mg: mean -1.00 versus -1.20 on control; difference 0.20 (95% CI -0.23 to 0.63), standardized effect d = 0.16; z-test p = 0.362.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TNX-601 ER, 39.4 mg and the control. The interval gives the range of effects that remain compatible with the data.

Sheehan Disability Scale (SDS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • TNX-601 ER, 39.4 mg: mean -5.80 versus -7.30 on control; difference 1.50 (95% CI -1.16 to 4.16), standardized effect d = 0.19; z-test p = 0.269.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TNX-601 ER, 39.4 mg and the control. The interval gives the range of effects that remain compatible with the data.

The two posted secondary outcomes are CGI-S and SDS, each reported for Day 1 and Week 6. Their group comparisons have the same broad pattern as the primary endpoint in one respect: the confidence intervals include zero, and the unadjusted p-values do not provide strong evidence of a between-group difference in the posted calculations. The registry record lists no reported sponsor analyses for either secondary outcome.

These outcomes capture measures distinct from the primary MADRS score. CGI-S is a severity rating, while SDS concerns disability. They can add context about symptom severity and functioning, but they are not interchangeable with the primary measure. Read together, the posted outcomes do not provide a clear pattern of separation between the groups that would change the overall interpretation of the primary comparison. The secondary findings should be considered alongside, not instead of, the primary endpoint.

General: Testing multiple outcomes creates multiplicity. When several comparisons are examined, the chance of at least one apparently notable result can increase, even when no true differences exist. Statistical adjustments or a prespecified hierarchy can address this issue, but the registry record does not report whether either approach was used. Because the secondary comparisons are reported as unadjusted and no analyses are listed, they carry less confirmatory weight than a prespecified, appropriately controlled analysis would.

Secondary outcomes can still be informative for describing the breadth and consistency of the posted results. Their interpretation is limited, however, by the absence of reported multiplicity procedures, analysis details, and information about missing data. They should not be treated as independent confirmation of the primary finding or as evidence that settles the treatment comparison.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Clinical Global Impression of Severity (CGI-S)
• Sheehan Disability Scale (SDS)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a least-squares mean describe?

The registry reports least-squares mean changes for the continuous MADRS endpoint. General: A least-squares mean is an estimate of a group mean produced by a statistical model. It may account for variables included in that model, but the registry record does not state which model or variables were used. The estimate should therefore be understood by its reported label, without assuming a particular adjustment strategy. The posted values are -12.8 for placebo and -12.7 for TNX-601 ER, 39.4 mg.

What is the between-group estimate?

The comparison is reported as a mean difference of 0.1 units, with TNX-601 ER compared against placebo. This is a contrast between the group estimates, not a separate within-group change. General: A between-group contrast is usually more relevant to a randomized comparison than asking whether each arm changed from baseline on its own. Change in both arms can occur, and the comparative estimate describes how far apart the observed group changes are.

The posted comparison is an unadjusted recalculation from the summary statistics. The underlying standard deviations are approximated from the standard errors reported for the least-squares means. This is not identified as a sponsor-reported inferential analysis; the registry record lists no reported analyses. The registry record does not describe a model-based treatment contrast or confirmatory testing procedure.

What does the standard error tell us?

The primary group standard errors are 1.32 for placebo and 1.3 for TNX-601 ER, 39.4 mg. General: A standard error describes the sampling variability of an estimated mean under the assumptions of the analysis. It is not the spread of individual participants' scores. A smaller standard error generally corresponds to a more precisely estimated group mean, but precision also depends on the analysis and data structure. The standard errors alone do not reveal the distribution of individual outcomes.

How should the p-value be read?

The unadjusted p-value for the primary comparison is 0.957. General: A p-value is calculated under a null hypothesis and a statistical model. It describes how compatible the observed data are with that model's predictions, in a way that depends on the model assumptions. It does not give the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The word unadjusted matters because this value is not reported as corrected for examining multiple outcomes or comparisons.

Why can over-dispersion matter?

General: Over-dispersion occurs when the variation in observed data is larger than a statistical model expects. If a method assumes less variability than is present, its standard errors can be too small and its intervals too narrow, making the evidence appear more precise than it is. This issue is especially relevant to some count-data models; the primary MADRS result is a continuous outcome, and the registry record does not report an over-dispersion assessment or a count-data model. It is therefore a general statistical consideration, not a documented finding for this trial.

What analysis details are not specified?

The registry record does not report the model used to obtain the least-squares means, covariates, assumptions checks, method for handling missing observations, or whether sensitivity analyses were performed. It also does not describe interim analyses or the prespecified statistical analysis plan. Those details can affect how estimates and uncertainty should be interpreted. Their absence from the registry record does not show that no such procedures existed; it means they cannot be characterized from the recorded information.

General: Statistical interpretation combines the estimated effect, its uncertainty, the design, and the analysis assumptions. A single estimate or p-value cannot substitute for those components. For this study, the posted summary statistics allow a descriptive comparison, but the limited analysis detail means the result should not be treated as a complete account of the sponsor's statistical analysis.

11. Confidence Intervals and Precision

The primary estimate is a mean difference of 0.1 MADRS units for TNX-601 ER, 39.4 mg, relative to placebo. Its 95% confidence interval extends from -3.531 to 3.731. A confidence interval is a range of values compatible with the estimate and the statistical method used. In repeated use under the method's assumptions, intervals constructed in this way would capture the true value at their stated rate. It is not a statement that there is a 95% probability that this particular interval contains the true effect.

The interval includes zero and extends in both directions. Thus, the posted estimate does not determine whether the between-group difference is positive or negative. Its width also means that the point estimate should not be read as a highly precise statement that the difference is exactly 0.1. The registry record does not report a threshold for clinical importance, so the interval cannot be judged against a trial-defined margin.

The confidence interval accompanies an unadjusted recalculation from the posted summary statistics, with standard deviations approximated from standard errors. The registry record lists no reported analyses for this endpoint and does not describe the sponsor's interval method. Precision should therefore be understood in the context of the available summary data and the approximations used, rather than as a substitute for a fully reported analysis.

General: Confidence intervals are useful because they pair an estimate with uncertainty, whereas a point estimate alone can give a misleading impression of certainty. Precision is not the same as clinical importance: a narrow interval may still center on a small effect, and a wide interval may leave several interpretations open. Here, the reported interval is the clearest indication of uncertainty around the primary comparison.

12. 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, not total events. They are illustrations based on the observed effect, not a report of the trial's original design assumptions. The registry record does not report the original sample-size justification. The listed illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers detecting the stated fraction of the observed effect.

The 80% power column describes the planned number of participants per arm under those assumptions for a design that would have an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column uses a higher target chance of detection under the same general planning framework. These are design probabilities under assumptions, not guarantees about what a study will find.

Rows representing a smaller fraction of the observed effect require more participants per arm than rows representing a larger effect. This is a general feature of planning: smaller differences are harder to distinguish from random variation, so more information is needed to detect them with the same target power. The listed calculations use the observed effect as their starting point, and the observed primary estimate is close to zero, so the resulting planning figures should be read cautiously as illustrations rather than as a practical recommendation or reconstruction of the trial's design.

This is not observed power. Observed power is not a useful substitute for interpreting the effect estimate and its confidence interval after a study; the planning figures instead describe hypothetical designs under stated assumptions. The registry record does not report whether the original trial used these assumptions or any of these target power levels.

13. 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 = 0.100; pooled standard deviation σ = 10.653.
2. n = 2 × (1.96 + 0.842)² × 10.653² / 0.100² = 178,138.8, rounded up to 178,139 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 <- 0.100000000000001                      # observed difference in means
sigma <- 10.6527188295542                     # 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(5686408)
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 = 178,139 (80% power), 238,478 (90% power)
 75% of observed effect: n per arm = 316,692 (80% power), 423,960 (90% power)
 50% of observed effect: n per arm = 712,556 (80% power), 953,910 (90% power)
power.t.test: 178139.8 
Simulated power at n = 178,139 per arm: 0.804 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and two secondary outcomes, but does not report a multiplicity strategy. It is not reported in the registry record whether the outcomes were tested in a hierarchy, whether family-wise error was controlled, or whether any secondary analyses were intended to be confirmatory. The posted p-values for the comparisons are unadjusted. When multiple outcomes or contrasts are examined, unadjusted p-values can overstate the strength of evidence if interpreted as though only one test had been considered.

The record also lists no reported analyses for the primary or secondary outcomes. The comparisons discussed are unadjusted recalculations from posted summary statistics, not a substitute for a reported statistical analysis plan. The registry record does not specify covariate adjustment, model structure, assumptions checks, sensitivity analyses, or interim analyses. It is not reported in the registry record whether these procedures were conducted outside the posted entry.

The primary population is described as the ITT population, including all randomized patients who received at least one dose of investigational product. This definition is narrower than a description that simply includes every randomized participant, because receipt of at least one dose is part of the stated criterion. The record does not report details of the analysis population for the secondary outcomes beyond the posted group summaries.

Missing-data handling is not reported in the registry record. There is no description of the amount or pattern of missing Week 6 measurements, any imputation procedure, or sensitivity analyses for missing outcomes. Without these details, it is difficult to judge how incomplete follow-up may have influenced the estimates. This does not establish that missing data occurred or that no method was used; it identifies information unavailable in the registry record.

These gaps matter because multiplicity, analysis population, model specification, and missing-data decisions can affect uncertainty and interpretation. The posted statistics remain descriptive evidence for the recorded outcomes, but they do not allow a full assessment of the planned inferential framework.

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: seizure (1.6%), generalized tonic-clonic seizure (1.6%), syncope (1.6%), dermatomyositis (1.5%).

The registry safety figures record serious adverse events among 68 participants at risk in the placebo group and 64 in the TNX-601 ER, 39.4 mg, group. One participant in the placebo group and two participants in the TNX-601 ER group were recorded as affected by a serious adverse event. No deaths were recorded in either group.

These are counts within the recorded groups, not estimates of comparative risk adjusted for follow-up or other factors. The registry record does not provide event-level details in these group totals, nor does it explain how relatedness was assessed. The listed serious event terms should not be assumed to belong to a particular arm unless the record explicitly links them to one.

Serious adverse event counts are distinct from counts of other adverse events and do not describe every aspect of safety or tolerability. They also do not establish whether an event was caused by the study drug. The figures should be read as a limited summary of events recorded during the study, not as a complete safety assessment or a basis for conclusions beyond the registry information.

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

The primary result describes a Week 6 comparison of MADRS change in the ITT population as defined by the registry. The posted least-squares mean changes were similar in magnitude, and the estimated between-group difference was 0.1 units. The confidence interval includes values on either side of zero, so the result does not precisely identify the direction or size of the difference. The unadjusted p-value is 0.957.

This result does not prove that the groups were identical, and it does not establish that any possible difference is clinically important or unimportant. The registry record does not provide a clinical-importance threshold for MADRS. The estimate and interval should be read together: the estimate is close to zero, while the interval indicates uncertainty around it. The posted data alone cannot resolve every value compatible with that uncertainty.

The endpoint is a score change over a limited study timeframe. It does not, by itself, answer questions about outcomes beyond Week 6, effects on every aspect of MDD, or longer-term safety. The registry record reports secondary measures of severity and disability, but those comparisons are unadjusted and no sponsor analyses are listed.

The safety figures record serious adverse events and deaths, but they are not a complete accounting of all possible harms and do not establish causation. Likewise, the enrollment and group summaries do not provide enough information to assess every aspect of missing data or protocol adherence.

Overall, the posted statistics support a cautious description of the measured groups and their uncertainty. They should not be converted into a broad claim that TNX-601 ER does or does not work. The interpretation is confined to the recorded comparison, endpoint, population, and timeframe, with important analysis details not reported in the registry record.

17. Why This Trial Matters Statistically

This trial illustrates why an estimated treatment contrast should be read alongside its uncertainty. The primary point estimate is close to zero, but the confidence interval is more informative than the point estimate alone because it shows that the comparison is not precisely determined by the posted data. Reporting both values prevents a near-zero estimate from being mistaken for proof of equivalence.

It also highlights the difference between a descriptive summary and a fully reported analysis. The registry gives group least-squares means, standard errors, and a comparison, while listing no reported analyses. The comparison discussed is an unadjusted recalculation from summary statistics, with standard deviations approximated from standard errors. That distinction is important when interpreting p-values and intervals, since analysis choices and assumptions affect inferential results.

The study also shows why planning illustrations should not be confused with a study's original sample-size rationale. The planning figures use the observed effect and stated assumptions, while the registry record does not report the original design justification. Such calculations can show how required sample size changes with the target effect, but they cannot establish that the completed study was planned that way or that it had a particular probability of success.

Finally, the record's limited reporting on multiplicity, missing data, and analysis methods illustrates how registry summaries can leave uncertainty about the inferential framework. These are not merely technical details: they shape how confidently readers can interpret a statistical comparison. The trial is therefore a useful example of reading estimates, uncertainty, planning assumptions, and reporting gaps together rather than relying on a single result.

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 entry does not report the sponsor's statistical analyses for the primary or secondary outcomes. The displayed comparisons are unadjusted recalculations from summary statistics, and the primary calculation uses standard deviations approximated from reported standard errors. The registry does not describe the model underlying the least-squares means or a sponsor-reported method for estimating treatment contrasts.

The record does not report a sample-size justification for the original design, so the planning illustrations based on the observed effect cannot be treated as a reconstruction of the trial's planned power. It also does not report a multiplicity approach, missing-data methods, sensitivity analyses, interim analyses, or a detailed statistical analysis plan.

Although the primary endpoint is defined with a scale range and direction, no threshold for clinical importance is reported. This limits interpretation of the estimated difference in relation to a registry-defined clinical benchmark. The available outcome timeframe is Week 6; the entry does not provide the basis for conclusions about longer-term outcomes.

The registry uses both a double-blind description in the study title and a quadruple masking classification in the masking field. Further detail about masking is not reported in the registry record. The safety summary gives serious-event counts and deaths but does not, in those group totals, provide a complete account of event attribution or all safety outcomes. These limitations constrain interpretation of the posted record; they do not establish that unreported procedures or information were absent from the full study documentation.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study to Evaluate TNX-601 ER Monotherapy Versus Placebo in Patients With Major Depressive Disorder (MDD) — NCT05686408.
• Registry record last updated 2025-02-17; status last verified 2025-01.
• Results first posted 2025-02-17.
• 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

NCT05686408 is a completed Phase 2 randomized, placebo-controlled, parallel-group study of TNX-601 ER monotherapy in patients with MDD. The registry lists 132 participants enrolled. TNX-601 ER, 39.4 mg, and placebo were each taken orally once daily for 6 weeks.

The primary endpoint was change from baseline in MADRS total score at Week 6. The posted group changes were -12.8 for placebo and -12.7 for TNX-601 ER, with a mean difference of 0.1 and a confidence interval from -3.531 to 3.731. The registry lists CGI-S and SDS as secondary outcomes.

The registry record lists no reported analyses and does not report the original sample-size justification, multiplicity procedure, missing-data method, or detailed statistical model. The posted comparison is best interpreted as a summary-based, unadjusted estimate with uncertainty, rather than as a complete account of the study's statistical analysis.