This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Open-Label Safety Study of AXS-05 in Subjects With TRD (EVOLVE) (NCT04634669), a na phase 2 study. The primary outcome is Incidence of Treatment-emergent AEs (TEAEs) Following Dosing With AXS-05.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04634669 |
| Phase | Phase 2 |
| Condition | Treatment Resistant Depression, Major Depressive Disorder |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 181 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Axsome Therapeutics, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
The study enrolled subjects with major depressive disorder and prior treatment failures; the listed conditions are Treatment Resistant Depression and Major Depressive Disorder. The registry reports enrollment of 181. Further eligibility criteria and characteristics of the participants are not reported in the registry record.
Intervention
Participants received AXS-05, identified as dextromethorphan-bupropion. The study was open-label, so masking was none. The registry describes the study as evaluating long-term safety and efficacy. Duration of participation was up to 15 months.
Comparator
There was no concurrent comparator group. The allocation is listed as not applicable, and the study model is single group. Accordingly, the registry record does not support a like-for-like comparison between AXS-05 and another treatment or control condition.
Primary question
The primary endpoint asks how many participants experienced treatment-emergent adverse events (TEAEs) following dosing with AXS-05. A TEAE was defined as an adverse event with an onset from the first study-treatment dose through 7 days after the last dose. The registry also describes the broader aim as assessing long-term safety and efficacy, but a posted efficacy result is not reported in the registry record.
In statistical terms, the primary question is descriptive: what participant count was recorded for TEAEs during the specified treatment-related observation window? Without a concurrent control group, the study cannot directly estimate how that count compares with what would have occurred under another treatment or no study treatment. The open-label design also means participants and investigators knew the treatment being given, which can affect how events are noticed, reported, or assessed. Those features do not invalidate the recorded safety information, but they shape the conclusions it can support.
3. Trial Design
EVOLVE (NCT04634669) is listed as a Phase 2, multicenter, open-label, single-group study of AXS-05 in subjects with treatment-resistant depression. The intervention is identified as dextromethorphan-bupropion. The registry reports enrollment of 181. Allocation is listed as not applicable, masking as none, and the model as single group. There is therefore no randomized allocation or blinded comparison described in the record.
The study began on 2020-09-23, and its primary completion date is 2022-02-18. Its status is terminated. The reason for termination is not reported in the registry record, so the status alone does not explain whether the study ended earlier than intended, whether recruitment or follow-up was affected, or what prompted the decision. Duration of participation was up to 15 months; the record does not give individual follow-up durations or explain how long participants actually remained under observation.
The registry lists safety and efficacy as the broad aims, while the primary outcome is the incidence of TEAEs. The outcome is expressed as a participant count. A participant-count endpoint is different from a count of every event: a participant may experience more than one event, but the endpoint as described concerns participants with events. The posted registry information does not give the primary endpoint result or an efficacy analysis. It lists adverse-event figures separately, which can inform a descriptive reading of recorded safety events but do not constitute a controlled comparison.
Because the study has one treatment group, any changes observed during participation cannot be separated from changes that might have occurred over time for other reasons. The design can describe events recorded among participants receiving AXS-05, but it cannot establish a comparative treatment effect. The registry record does not report a protocol rationale for choosing the design or a sample-size justification.
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
| Stage | AXS-05 |
|---|---|
| STARTED | 181 |
| COMPLETED | 11 |
| NOT COMPLETED | 170 |
Reasons for not completing this period:
| Reason | AXS-05 |
|---|---|
| Study Terminated by Sponsor | 95 |
| Withdrawal by Subject | 20 |
| All Other Reasons | 55 |
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | AXS-05 |
|---|---|---|
| Participants analysed | 181 | |
| Age, Continuous | years | 46.6 (SD 13.1) |
| Sex: Female, Male: Female | Participants | 113 |
| Sex: Female, Male: Male | Participants | 68 |
| Race/Ethnicity, Customized: White | Participants | 144 |
| Race/Ethnicity, Customized: Black or African American | Participants | 29 |
| Race/Ethnicity, Customized: Asian | Participants | 3 |
| Race/Ethnicity, Customized: Other | Participants | 3 |
| Race/Ethnicity, Customized: Multiple | Participants | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Incidence of Treatment-emergent AEs (TEAEs) Following Dosing With AXS-05, measured over Duration of participation was up to 15 months. TEAEs were defined as any AE with an onset date in the interval between the first study treatment dosing date and 7 days after the last study treatment dosing date..
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is titled “Incidence of Treatment-emergent AEs (TEAEs) Following Dosing With AXS-05.” Its unit is participants, and the parameter is a count of participants. A TEAE is defined by its timing: an adverse event with an onset between the first study-treatment dose and 7 days after the last study-treatment dose. Participation could last up to 15 months, so the observation window is tied to each participant’s dosing dates rather than stated as one fixed follow-up period for everyone.
This kind of endpoint is used to describe how many participants had at least one event during the defined period. In general, participant counts can communicate how widespread an event experience was in a study group, while event counts answer how many event occurrences were recorded. These are not interchangeable: one participant may have multiple events, and the participant count does not convey the number of events per participant, their duration, or their clinical course.
The endpoint title and definition identify what should be counted, but the primary outcome result is not reported in the registry record. The registry does list adverse-event figures, including serious and other adverse events, but those entries should not be treated as a posted result for the primary TEAE endpoint unless the record explicitly connects them to that endpoint. The endpoint is descriptive and, in a single-group open-label study, does not by itself estimate a comparative safety effect.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes an open-label, single-group study of AXS-05 and lists enrollment of 181. The primary outcome concerns participants with TEAEs during the period from the first dose through 7 days after the last dose. However, a numerical result for that primary outcome is not reported in the registry record. The adverse-event listing separately reports 7 participants with serious adverse events and 38 with other adverse events; both entries list 181 at risk. It also reports 0 deaths. These are descriptive safety figures, not a randomized comparison.
The serious adverse-event listing includes Inappropriate antidiuretic hormone secretion, Cholecystitis, COVID-19 pneumonia, Coronavirus infection, Urinary tract infection, and Procedural pain, each listed with 0.6%. The record does not provide further detail in the registry record about event timing, severity beyond the serious classification, management, recurrence, or attribution. The displayed percentages should be read as registry entries, not as evidence that an event was caused by AXS-05.
In general, results from a single-group study describe what was recorded among participants who received the intervention. They do not isolate the intervention’s contribution from other explanations, such as the underlying condition, participants’ prior or concurrent circumstances, or changes over time. An open-label design can also affect event reporting and assessment. These limitations are particularly relevant when interpreting adverse events, which may involve judgments about whether an event occurred and how it should be classified.
No confidence interval, hypothesis test, adjusted estimate, or analysis result is reported in the registry record. A confidence interval, in general, expresses uncertainty around an estimate; without one, the precision of the reported participant counts cannot be assessed through an interval estimate. The counts remain informative descriptions of the registry-listed group, but they do not establish how those counts would compare with a control group or another treatment.
The registry status is terminated, but the reason is not reported in the registry record. It is not possible to infer from that status alone whether the termination changed the planned follow-up or analyses. Nor is a posted efficacy result available in the record. The safest statistical reading is therefore limited: the registry lists specific adverse-event counts and terms, while the primary TEAE outcome result and comparative analyses are not reported.
9. Statistical Methods Explained
The main methodological feature is the single-group design. All participants in the listed study group received AXS-05, and the registry does not identify a concurrent control arm. In general, a single-group study can estimate or describe outcomes within that group, but it cannot directly estimate a contrast between treatment conditions. Any before-and-after change, if one were reported, could reflect the intervention, the natural course of the condition, other influences, or measurement processes. No before-and-after efficacy result is reported in the registry record.
What does an open-label design imply?
Open-label means masking was none: participants and study personnel were not blinded to the treatment assignment. In general, lack of masking can influence which symptoms are reported, how they are elicited, and how events are interpreted or classified. This matters for safety reporting because event detection and classification may involve judgment. It does not mean that an event is inaccurate, but it is one design feature to consider when interpreting descriptive counts. The registry does not report procedures used to reduce reporting or assessment differences.
What is the event-count endpoint?
The primary endpoint uses a count of participants with TEAEs, not a count of all event occurrences. Its time definition begins with the first study-treatment dose and ends 7 days after the last dose. In general, a participant-level event endpoint records whether a participant experienced an event during the defined window. It does not, on its own, describe how many events an affected participant experienced, how long they lasted, or how their severity changed. The registry record does not report a numerical result for this primary endpoint.
The adverse-event entries give 7 participants with serious adverse events and 38 with other adverse events, with 181 at risk in each listing, and 0 deaths. These entries are descriptive. The available information does not establish whether the serious and other categories are mutually exclusive, nor does it describe event-level counts or follow-up time for each participant. For that reason, the entries should not be combined or interpreted as a complete breakdown of the primary TEAE endpoint.
How should uncertainty be understood?
In general, a confidence interval gives a range of estimates compatible with the observed data under a statistical method. Its width reflects statistical uncertainty, with wider intervals indicating less precision. No confidence interval for the primary outcome or adverse-event counts is reported in the registry record. Without an interval or other inferential analysis, readers can describe the listed counts but cannot use the registry entry to assess their precision through an interval estimate.
A hypothesis test, in general, evaluates data against a specified null hypothesis under stated assumptions. The registry record reports no analysis results and lists 0 analyses. It does not report a hypothesis, test statistic, p-value, adjusted model, or inferential plan. A lack of reported testing is not evidence of no effect; it means the record does not present a statistical test to interpret.
What does the planning illustration represent?
The planning method described uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. It is described as a planning illustration computed from the observed effect, not as the trial’s own design. The underlying study is single-group, so this hypothetical two-arm planning framework is not a description of the study’s allocation or an observed comparison. The record does not report numerical planning estimates in the information available for this analysis.
In general, a sample-size calculation estimates how many participants a future study might need under specified assumptions. Such a calculation depends on the target effect, variability or event frequency, significance level, power target, allocation, and analysis method. If assumptions change, the planning estimate can change as well. Planning estimates are not observed power: they do not measure the probability that the completed study detected an effect after results are known. The registry record does not report the protocol’s sample-size justification or enough results to reconstruct one.
For event data, general statistical methods may account for the fact that individual participants can experience events with different frequencies. Over-dispersion describes more variation in counts than a simpler model assumes; if present, ignoring it can make uncertainty appear too small. The registry information does not provide event-level counts or a model for repeated events, and it does not report an analysis addressing over-dispersion. This is a general methodological consideration, not a claim about the analysis performed in this study.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists one primary outcome measure and 0 analyses. It does not report a statistical analysis plan, a multiplicity adjustment, or a hierarchy of secondary outcomes. Multiplicity arises in general when several hypotheses or outcomes are tested: the chance of at least one false-positive result can increase as tests accumulate. Adjustments or pre-specified testing strategies can address that issue, but no such approach is reported. Since no hypothesis-test results are listed, there are no reported p-values to interpret in light of multiplicity.
Missing-data handling is not reported in the registry record. The entry does not describe how participants who stopped treatment, withdrew, missed assessments, or had incomplete adverse-event follow-up were handled for the primary endpoint. The termination status does not, by itself, indicate that data were missing or explain how any incomplete records were treated. Duration of participation was up to 15 months, but individual observation time and follow-up completeness are not given.
The analysis population is not reported in the registry record. Although enrollment is listed as 181 and the adverse-event entries list 181 at risk, the available information does not define whether the primary analysis included everyone enrolled, everyone who received at least one dose, or another population. Nor does it provide a participant flow or explain exclusions. It is therefore not possible to determine from the record whether the adverse-event denominator and the intended primary endpoint population were defined identically.
In general, missing-data rules and analysis-population definitions affect how an estimate should be interpreted. Excluding participants with incomplete follow-up can change the group represented by a result; different assumptions about unobserved outcomes can also affect an analysis. Without the relevant definitions, no particular handling method should be assumed. The registry entry leaves these details unreported.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| AXS-05 | 7 | 181 | 3.9% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| AXS-05 | 0 of 181 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| AXS-05 | 38 of 181 |
Most frequent serious adverse event terms
| Event term | Organ system | AXS-05 |
|---|---|---|
| Inappropriate antidiuretic hormone secretion | Endocrine disorders | 1 of 181 |
| Cholecystitis | Hepatobiliary disorders | 1 of 181 |
| COVID-19 pneumonia | Infections and infestations | 1 of 181 |
| Coronavirus infection | Infections and infestations | 1 of 181 |
| Urinary tract infection | Infections and infestations | 1 of 181 |
| Procedural pain | Injury, poisoning and procedural complications | 1 of 181 |
| Hyponatraemia | Metabolism and nutrition disorders | 1 of 181 |
| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | 1 of 181 |
| Gastric cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 181 |
| Metabolic encephalopathy | Nervous system disorders | 1 of 181 |
Most frequent non-serious adverse event terms
| Event term | Organ system | AXS-05 |
|---|---|---|
| Covid-19 | Infections and infestations | 15 of 181 |
| Nausea | Gastrointestinal disorders | 15 of 181 |
| Headache | Nervous system disorders | 12 of 181 |
Serious events with the highest arm-level rate: inappropriate antidiuretic hormone secretion (0.6%), cholecystitis (0.6%), covid-19 pneumonia (0.6%), coronavirus infection (0.6%), urinary tract infection (0.6%).
The adverse-event listing reports 7 participants with serious adverse events and 38 with other adverse events; each entry lists 181 at risk. It reports 0 deaths. These figures describe what the registry records for the AXS-05 group. They are not a comparison with an untreated group or another treatment, and they do not establish that AXS-05 caused any event. The record does not explain whether participants could appear in both the serious and other categories, so the counts should not be added together.
The listed serious-event terms are Inappropriate antidiuretic hormone secretion, Cholecystitis, COVID-19 pneumonia, Coronavirus infection, Urinary tract infection, and Procedural pain. Each is listed with 0.6%. Those percentages are presented as registry entries; the available record does not give additional event-level detail or explain the relation between each term and participant-level counts.
In general, an adverse-event listing is a safety description, not necessarily a causal assessment. “Serious” is a classification of an event and should not be read as a measure of how likely treatment was to have caused it. The open-label, single-group design and the absence of a comparator limit causal interpretation. The registry does not report a numerical result for the primary TEAE endpoint, so these safety entries should remain distinct from that endpoint rather than being treated as its complete result.
12. What the Result Does, and Does Not, Mean
The registry record establishes that EVOLVE was an open-label, single-group Phase 2 study of AXS-05 in subjects with treatment-resistant depression, with enrollment of 181 and participation lasting up to 15 months. It lists a primary endpoint based on participants with TEAEs within the treatment-related observation window. The record also lists 7 participants with serious adverse events, 38 with other adverse events, and 0 deaths. These values are descriptive records for the study group.
They do not show how the same participants would have fared under a different treatment or without study treatment. There is no concurrent comparator group, and the study was not randomized or masked. As a result, the record cannot establish a comparative treatment effect or determine whether AXS-05 caused the events listed. The numbers also do not describe the number of event occurrences per participant, event duration, or the full course of follow-up.
The primary TEAE result, an efficacy result, and inferential analyses are not reported in the registry record. Thus, the reported adverse-event figures cannot answer whether a specified treatment effect occurred, how precisely it was estimated, or whether any observed outcome differs from an alternative condition. No confidence interval or hypothesis test is available to quantify uncertainty around the listed outcomes.
The study status is terminated, but the reason is not reported in the registry record. That status should not be used to infer a particular safety finding, efficacy finding, or operational problem. The record also does not report missing-data methods, analysis populations, or a protocol-based sample-size justification. Those omissions restrict interpretation of completeness and precision.
In general, a descriptive safety record can be useful for understanding which events were recorded in a study group and what categories were listed. Its meaning depends on the event definitions, follow-up, assessment methods, and participant population. Here, the defensible conclusion is limited to the registry-listed counts and terms; stronger comparative or causal claims are not supported by the design and reported statistical information.
13. Why This Trial Matters Statistically
This study is statistically informative as an example of the distinction between describing outcomes and estimating comparative effects. EVOLVE has a single treatment group, with no randomized control condition and no masking. The registry can record safety events among participants receiving AXS-05, but the design does not provide the contrast needed to separate treatment-associated outcomes from other influences. Recognizing that distinction helps prevent descriptive event counts from being interpreted as evidence of comparative benefit or harm.
The primary endpoint is a participant count defined over a treatment-related time window. That definition illustrates why endpoint construction matters: counts of participants with at least one event answer a different question from counts of all event occurrences. The registry also presents serious and other adverse-event counts separately. Without further detail about event-level records, category overlap, or follow-up completeness, those summaries should be read within their stated limits rather than combined into a broader total.
The record’s missing analysis details are also important. It lists no analyses, and does not report confidence intervals, hypothesis tests, missing-data methods, or the analysis population. These omissions prevent readers from assessing statistical precision or determining the exact population represented by the primary endpoint. The terminated status adds context, but the reason is not reported and cannot be inferred from the label alone.
Finally, the stated planning illustration uses a hypothetical two-arm framework, while the actual study is single-group. That distinction makes clear that planning assumptions are not equivalent to the trial’s design and should not be mistaken for observed power. Together, these features show why sound interpretation depends on matching each statistical claim to the design, endpoint, and analysis details that are actually reported.
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 absence of a comparator is the central design limitation for causal interpretation. Outcomes recorded in the AXS-05 group cannot be directly contrasted with outcomes under another treatment or control condition. The open-label design introduces additional potential for differences in event reporting and assessment. These features do not erase the descriptive safety information, but they limit conclusions about attribution and comparative effects.
The registry record does not report the primary TEAE result, an efficacy result, confidence intervals, hypothesis tests, or other analyses. It also does not report an analysis population, missing-data methods, or a participant-flow account. Consequently, the completeness of the endpoint data and the precision of estimates cannot be assessed from the available information. The adverse-event entries should not be assumed to be the full primary endpoint result.
The adverse-event listing does not clarify whether participants could be represented in both serious and other categories, or provide detailed event-level information, individual follow-up, or attribution assessments. Although the duration of participation was up to 15 months, actual follow-up time for participants is not reported. The record status is terminated, but its reason and any consequences for planned follow-up or analysis are not reported in the registry record.
The registry also does not report the protocol’s sample-size justification or its statistical analysis plan. The described planning illustration uses assumptions for a hypothetical two-arm study, which differs from the single-group design. Without its numerical estimates and complete underlying assumptions, it should not be read as a statement of the study’s design adequacy or observed power.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Open-Label Safety Study of AXS-05 in Subjects With TRD (EVOLVE) — NCT04634669.
- Registry record last updated 2026-01-28; status last verified 2026-01.
- Results first posted 2026-01-28.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT04634669, titled “Open-Label Safety Study of AXS-05 in Subjects With TRD (EVOLVE),” is a Phase 2, multicenter, open-label, single-group study sponsored by Axsome Therapeutics, Inc. It enrolled 181 subjects and evaluated AXS-05 (dextromethorphan-bupropion). The study began on 2020-09-23, had a primary completion date of 2022-02-18, and is listed as terminated.
The primary endpoint is the count of participants with TEAEs, defined as events beginning between the first study-treatment dose and 7 days after the last dose. Participation was up to 15 months. The registry lists 7 participants with serious adverse events, 38 with other adverse events, and 0 deaths, with 181 at risk in each adverse-event listing. The primary endpoint result, efficacy results, reason for termination, and statistical analyses are not reported in the registry record.