A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder (NCT03093025), a randomized phase 2 study. The primary outcome is Montgomery-Asberg Depression Rating Scale (MADRS).

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, parallel-group study of TS-121 as an adjunctive treatment for participants with major depressive disorder and an inadequate response to current antidepressant treatment. The official title describes it as multicenter, double-blind, and placebo-controlled. The registry identifies the masking as triple. The three groups received TS-121 10mg, TS-121 50mg, or placebo.

The registry record reports enrollment of 51 participants. For the primary MADRS outcome at six weeks, results are reported for 13 participants in the 10mg group, 15 in the 50mg group, and 17 in the placebo group. Those analysis counts do not account for all enrolled participants. The primary-outcome analysis population excluded participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessment. Further reasons for the difference between enrollment and analysis counts are not reported in the registry record.

The safety results use different group counts: 16 participants at risk in each TS-121 group and 18 in the placebo group. The registry status is terminated. The reason for termination, the timing of that decision, and whether the study stopped according to its original plans are not reported in the registry record. The record gives a study start date of 2017-07-03 and a primary completion date of 2018-11-08.

The study description says its purpose was to evaluate safety, tolerability, and efficacy. It lists several clinical rating measures as secondary outcomes. The registry record does not report the full protocol, detailed allocation procedures, or the rationale for the planned enrollment.

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: Participants who did not receive at least one dose of investigational product or did not have at least one post-dose assessments were not included in the analysis.

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 6 weeks.

The primary endpoint was the Montgomery-Asberg Depression Rating Scale (MADRS), reported as a least-squares mean with a 95% confidence interval at six weeks. MADRS is a clinician-rated measure of depressive symptoms over the past 7 days. It consists of 10 items, each scored on a 7-point scale from 0 for absence of symptoms to 6 for severe symptoms. The total score is the sum of the item scores and ranges from 0 to 60. A negative change from baseline indicates improvement.

A continuous score preserves gradations in symptom ratings, rather than reducing each participant’s result to a simple responder or non-responder category. Least-squares means generally refer to model-based group estimates, but the registry record does not describe the model used to obtain these estimates or its covariates. The registry reports group-level estimates and confidence intervals; it does not report a primary between-group estimate or a test of the difference between groups.

Using a clinician-rated symptom scale gives the trial a defined way to quantify change over the stated assessment period. However, the arm-level estimates alone do not show how the groups compare after accounting for the trial’s analysis plan. The scale’s definition explains what the outcome represents, while the missing details about the statistical model limit how fully the estimates can be interpreted.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean represent?

A least-squares mean is commonly a model-based estimate of a group’s average outcome. It can differ from a simple arithmetic average when the statistical model accounts for other variables or features of the design. The registry record reports least-squares mean MADRS results but does not describe the model, any adjustment variables, or how missing observations were handled. As a result, the estimates can be quoted as posted, but the details needed to reproduce or fully assess their adjustment are not reported in the registry record.

The reported MADRS confidence intervals describe uncertainty around each arm-level estimate. In general, a confidence interval is a range produced by a statistical procedure that reflects sampling uncertainty under the method’s assumptions. It does not mean that all values in the interval are equally likely, nor does it directly answer whether one treatment group differs from another. For that question, a between-group estimate and its uncertainty are needed. Those primary between-group results are not reported in the registry record.

How should the binary comparisons be read?

The secondary outcome percentages describe the proportion of participants meeting the recorded outcome in each group. A risk difference expresses the difference between two such proportions, with the sign depending on the order of subtraction. Its confidence interval describes uncertainty in that difference. When an interval includes zero, the posted summary statistics are compatible with no difference as well as with differences in either direction under the calculation used.

The risk differences, confidence intervals, and p-values discussed for MADRS and CGI-I are unadjusted recalculations from posted summary statistics. They are not analyses reported by the sponsor in the registry record. The record does not provide the sponsor’s analysis methods for those outcomes. There is no reported discrepancy between the recalculations and sponsor analyses, but the recalculations should still be understood as simple, unadjusted comparisons rather than as substitutes for a prespecified model.

A p-value summarizes how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical procedure. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. These recalculated p-values are unadjusted. Because the study includes more than one dose and more than one secondary outcome, interpreting each p-value in isolation can overstate the strength of evidence. The registry record does not report a multiplicity strategy for these results.

Why do small groups affect precision?

Estimates from small groups can vary substantially from one sample to another. For a continuous outcome, this can produce wide uncertainty around an estimated mean. For a binary outcome, the estimate may depend strongly on only a few participants’ outcomes. The posted confidence intervals for the secondary risk differences are broad, illustrating the uncertainty in these comparisons. The registry record does not report a formal precision target for the primary outcome.

Over-dispersion is a general statistical concern when observed variability exceeds what a model assumes. If a method does not allow for that extra variability, its uncertainty estimates may be too narrow. The registry record does not report whether over-dispersion was assessed or relevant to the primary analysis; no claim about its presence can be made from the posted results.

What do the planning illustrations mean?

The sample-size illustrations use the observed effect as a planning reference and show calculations for detecting stated fractions of that effect. They assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are planning illustrations, not the trial’s own design justification and not observed power. The record does not report the original sample-size assumptions or justification, so the illustrations cannot establish whether the study was planned to detect a particular effect.

Planning calculations that use an observed effect can be unstable, especially when the initial estimate comes from small groups. A smaller assumed effect generally requires more participants to detect it under otherwise similar assumptions. The illustrations can therefore help readers understand how different target effects relate to sample-size requirements, but they do not show what the study would have found with a different enrollment or what probability it had of detecting the true effect.

What remains unknown about the analysis?

The registry record does not report the primary between-group model, the handling of missing outcome data, any interim analyses, or the intended multiplicity procedure. It also does not provide a detailed account of the analysis populations beyond the stated primary-outcome exclusion criterion. These omissions matter because they affect how estimates and tests should be interpreted. The posted arm-level results remain useful descriptions, but they do not supply the full analysis framework needed to independently evaluate every inferential choice.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical plan describing how the study handled multiplicity. The study has two TS-121 dose groups, a placebo group, and multiple outcome measures. Considering several comparisons can raise the chance that at least one result appears noteworthy by chance, even when no true difference exists. Methods for controlling or otherwise addressing multiplicity depend on the planned hypotheses and analysis strategy; those details are not reported in the registry record.

The recalculated secondary p-values are unadjusted. They do not account for the set of outcomes and comparisons considered. They should not be interpreted as if they were a single prespecified test. The registry record also does not report sponsor analyses for these secondary outcomes or a hierarchy of primary and secondary hypotheses beyond identifying the primary MADRS outcome.

Missing-data handling is also not reported in the registry record. The primary analysis population excludes participants who did not receive at least one dose or did not have at least one post-dose assessment. The record does not describe how other missing measurements were treated, whether any imputation was used, or whether sensitivity analyses were performed. It does not identify the primary analysis population using a fuller statistical definition.

These details affect the interpretation of precision and potential bias. If outcome availability differs across groups or is related to participants’ outcomes, an analysis limited to participants with observed assessments may not represent all randomized participants in the same way. The registry record does not provide enough information to determine whether this occurred or how it was addressed. Interim analyses and any associated decision rules are not reported in the registry record.

11. 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 posted safety results report zero serious adverse events in each group and zero deaths. The groups at risk were 16 participants for TS-121 10mg, 16 for TS-121 50mg, and 18 for placebo. These figures describe the recorded events among the participants included in the safety counts; they do not prove that serious events cannot occur.

Other adverse events affected 7 participants in each TS-121 group and 8 in the placebo group. The registry record does not provide event terms in the serious-event listing, which is empty. These counts do not describe severity, timing, duration, or the number of events per participant. The record also does not provide enough detail to evaluate differences in exposure or follow-up.

Safety counts from groups of this size are imprecise. Zero observed serious events means none were recorded in these participants during the reported study, not that the underlying risk is zero. The termination status is recorded, but its reason is not reported in the registry record; it should not be attributed to safety or any other cause without further information.

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

The registry record gives six-week arm-level MADRS estimates and confidence intervals, along with selected secondary outcome percentages. The primary scale description indicates that negative change from baseline represents improvement. The reported group estimates are therefore interpretable as changes in that direction, but the registry does not provide the primary between-group estimates needed to quantify how either TS-121 group compared with placebo.

The secondary results offer descriptive comparisons, but their recalculated confidence intervals include zero and the recalculated p-values are unadjusted. The record does not state how these analyses fit into a prespecified testing strategy. The available results therefore do not establish a definitive difference between groups. Nor do they establish that the groups are equivalent: absence of a reported statistically persuasive comparison is not evidence that the treatments have identical effects.

These findings also do not answer every question about efficacy or safety. The reported outcomes cover a stated assessment period, and the registry record does not describe longer-term results. The small numbers in each group limit precision, particularly for binary outcomes and uncommon safety events. The safety record reports no serious adverse events or deaths in the groups at risk, but this observation cannot rule out uncommon events.

The record identifies the study as terminated but does not state why. It also does not report the original sample-size rationale, detailed analysis plan, missing-data methods, or multiplicity procedures. Those gaps prevent a complete assessment of how the study was designed to make its primary inference. The most defensible reading is descriptive: the registry reports arm-specific estimates and selected outcomes, while leaving the central formal comparison and several important analysis details unreported.

13. Why This Trial Matters Statistically

This trial illustrates why arm-level estimates are not the same as a treatment comparison. A confidence interval around each group’s mean describes uncertainty about that group estimate. To assess the difference between TS-121 and placebo, readers need an estimate of the contrast and its uncertainty, produced using the intended analysis. The registry record reports the former but not the latter for the primary outcome.

It also shows how outcome format affects interpretation. MADRS is presented as a continuous score for the primary endpoint and as a percentage for a secondary outcome. The continuous summary retains information about score changes, whereas a percentage reduces outcomes to a category. These summaries can complement each other, but they should not be treated as identical analyses or interchangeable evidence.

The registry’s secondary comparisons make another statistical point: unadjusted results across multiple doses and outcomes need cautious interpretation. An isolated p-value cannot account for the broader set of questions being examined. The planning illustrations are similarly easy to misread. They are based on observed effects and stated assumptions, and they do not represent the study’s original sample-size plan or its observed power.

Finally, the difference between enrollment, primary analysis counts, and safety counts emphasizes the importance of clearly described analysis populations. The record gives one exclusion criterion for the primary analysis but does not report fuller missing-data methods. Together, these features make transparent reporting of estimates, analysis populations, and prespecified methods essential for evaluating a clinical trial.

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 results are reported by group, without a primary between-group estimate, confidence interval, or p-value in the registry record. The least-squares mean model and any adjustments are not described. This limits the ability to assess the intended primary comparison or reproduce the analysis.

The primary analysis counts are smaller than the enrollment count, and the registry record does not report the reasons for all differences between those counts. It states that participants without at least one dose or at least one post-dose assessment were excluded, but does not describe other missing-data handling, sensitivity analyses, or a fuller definition of the analysis population. The safety counts differ from the primary analysis counts, and the record does not explain the relationship between those populations.

The registry lists several secondary measures, but numerical results are not reported in the registry record for HAM-A, SDQ, or CGI-S. For the posted secondary comparisons, the recalculated tests are unadjusted, and the sponsor’s analysis methods are not reported. The multiplicity strategy is not reported, which limits the weight that can be placed on isolated secondary findings.

The record states that the study was terminated but does not report why. It also does not report the original sample-size justification or whether interim analyses occurred. The posted group sizes are limited, making estimates particularly uncertain for outcomes based on event counts. Safety reporting does not include serious-event terms or detailed event descriptions. These limitations are specific to the information available in the registry record and leave important questions unanswered about study conduct and interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder — NCT03093025.
• Registry record last updated 2020-07-14; status last verified 2020-07.
• Results first posted 2019-12-09.
• 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.

18. Record Summary

NCT03093025 is a randomized, triple-masked, parallel-group phase 2 study of TS-121 10mg and TS-121 50mg as adjunctive treatment for major depressive disorder, with placebo as comparator. The registry reports enrollment of 51 and a terminated status. The primary outcome was the six-week MADRS score, reported as least-squares mean estimates with 95% confidence intervals for each group. Formal primary between-group results are not reported in the registry record.

The record also posts selected secondary outcomes and safety counts. Recalculated secondary comparisons are unadjusted, and the registry does not report the full analysis plan, missing-data methods, multiplicity strategy, or reason for termination. The results are informative as arm-level descriptions, but their interpretation is limited by the absence of key comparative and methodological details.