Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD (NCT03051256), a randomized phase 2 study. The primary outcome is Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability].

2. Clinical Question

The registry describes a multicenter, randomized, double-blind, placebo-controlled, parallel study with three arms. Its stated focus includes safety, tolerability, pharmacokinetic profile, and symptom response. The primary outcome, however, is specifically the incidence of treatment-emergent adverse events. It therefore addresses reported or observed safety events over the stated assessment period, not whether depression symptoms improved.

The study summary frames the clinical question around adding REL-1017 to antidepressant treatment in adults whose current episode had not responded adequately to prior antidepressant courses. The comparison with placebo is intended to provide a reference for the added study treatment within that adjunctive setting. The registry record does not identify the background antidepressant or state how it was selected.

The posted outcome data list participants affected by other adverse events and serious adverse events for each arm. They do not provide a single comparative estimate or a statistical test for the primary outcome. The record also indicates that the primary outcome has several categories or time points and was not reduced to one comparison. As a result, the primary question can be described from the posted event counts, but a treatment-versus-placebo effect estimate for that endpoint is not reported in the registry record.

3. Trial Design

This was a Phase 2a, multicenter, randomized, parallel-group study. The official title describes it as double-blind and placebo-controlled; the registry's masking field is labeled triple. The registry record does not explain which roles were masked or how the masking labels correspond to one another. The study had three arms: REL-1017 25 mg, REL-1017 50 mg, and placebo.

The registry lists enrollment of 62. The study status is completed. The recorded study start date is 2018-05-11, and the primary completion date is 2019-07-30. The record describes the population as adults with major depressive disorder, a current major depressive episode, and an inadequate response to 1 to 3 courses of antidepressant treatment. The conditions field also lists treatment-resistant depressive disorder.

The intervention was adjunctive to antidepressant therapy. In the 25 mg arm, the registry describes 75 mg of powder in 100 mL of Ocean Spray Diet Cranberry Juice on Day 1, followed by 25 mg of powder in 100 mL daily on Day 2-7. In the 50 mg arm, it describes 100 mg of powder in 100 mL on Day 1, followed by 50 mg of powder in 100 mL daily on Day 2-7. The placebo arm received 100 mL of the juice daily for 7 days.

The primary outcome concerns treatment-emergent adverse events, with a timeframe of 21 days. Events were to be recorded if spontaneously reported or observed, and elicited with a non-leading question at each visit from Screening through the Day 21 assessment. The registry describes both in-patient and out-patient periods but does not report their timing or duration. Details of site locations, the randomization procedure, allocation concealment, and the identity of the background antidepressants are not reported in the registry record.

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: Safety population: All randomized patients who received any study treatment (REL-1017 or placebo).

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 Incidence of Treatment Emergent Adverse Events (AEs) [Safety and Tolerability], measured over 21 days.

The primary endpoint is the incidence of treatment-emergent adverse events, expressed as the number of participants affected. It is a safety and tolerability outcome: it records whether participants experienced adverse events during the study assessment period. It does not, by itself, establish that an event was caused by the investigational treatment.

The registry defines an adverse event broadly as an untoward medical occurrence in a person administered a pharmaceutical product. It may be a symptom, disease, unfavorable sign, or clinically significant laboratory abnormality associated in time with product use, whether or not it is judged related to treatment. The record also notes that an event could occur outside the time when the investigational product was given.

Events were to be recorded when spontaneously reported or observed, and elicited using a non-leading question at every visit from Screening through the Day 21 assessment. The endpoint timeframe is 21 days. The stated safety population comprises all randomized patients who received any study treatment, whether REL-1017 or placebo.

Counting affected participants is useful for describing how many people experienced events, rather than how many event episodes occurred. The count does not show the event types, severity, duration, or relationship to treatment for each participant. Those details are not reported in the primary outcome record. The posted primary outcome also has several categories or time points, so it is not presented as a single treatment comparison. No adjusted estimate or uncertainty interval for a single primary comparison is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Clinical trial results are easiest to interpret when the outcome, population, time window, and comparison are all explicit. In this study, the primary outcome is the number of participants with treatment-emergent adverse events, the stated population is the safety population, and the timeframe is 21 days. The registry defines the safety population as randomized patients who received any study treatment. Those elements describe what the endpoint is intended to count. They do not, by themselves, specify how missing observations were handled or how treatment groups were statistically compared.

What does a participant count represent?

A participant count records how many people experienced at least one event in the category being reported. It is different from a count of event episodes, because a participant may have more than one event. The primary endpoint is presented as a count of participants, and the adverse-event results separately report participants at risk and participants affected. The record does not provide event-level descriptions alongside these counts, so the number of affected participants cannot explain which events occurred or whether individual participants experienced multiple events.

Counts are descriptive. When group sizes differ, the raw count alone does not express the frequency of events in a comparable way. A rate or proportion can be useful for comparing groups, but calculating one would require deriving a new number from the posted counts. No such derived estimate is reported in the registry record. Nor does the record provide a confidence interval or a statistical test for the primary outcome. A reader should therefore distinguish the listed counts from an inferential comparison.

What would a confidence interval add?

In general, a confidence interval describes the uncertainty around an estimated quantity under a specified statistical method. For a treatment comparison, an interval can show which effect sizes are compatible with the observed data and the model assumptions. A narrow interval indicates greater precision than a wide interval, while an interval spanning effects in different directions may leave the direction or size of a difference uncertain. These are general statistical interpretations, not findings from this trial. A confidence interval for the primary comparison is not reported in the registry record.

Why does the comparison need to be defined?

A randomized, parallel-group design assigns participants to treatment arms so that outcomes can be compared across groups. Here, the arms are REL-1017 25 mg, REL-1017 50 mg, and placebo. A statistical analysis still needs to state which groups are being contrasted and which outcome category and time point are used. The registry says the primary outcome includes several categories or time points and was not reduced to one comparison. It does not report a single primary contrast, so there is no one posted treatment effect estimate to interpret.

General analysis choices can include comparing each active arm with placebo, comparing active doses with one another, or using a model that covers multiple groups. Each choice addresses a different question and can affect how uncertainty and multiplicity are handled. The registry record does not report which approach was used for the primary endpoint. No particular model, adjustment, or testing sequence should be assumed.

What is multiplicity?

Multiplicity arises when several hypotheses or outcomes are assessed. Repeated testing can increase the chance of at least one apparently notable result even when no underlying effect exists. Statistical plans can address this by prioritizing an outcome, adjusting significance thresholds, controlling a specified error rate, or treating analyses as exploratory. These are general options, not reported methods for this study. The registry lists 16 outcome measures and 16 analyses, and it does not report a multiplicity strategy for the results.

Why can adverse-event counts be difficult to compare?

Safety outcomes may include events with different causes, seriousness, timing, and clinical significance. Combining them into a count of participants with any event is a compact description, but it can conceal those differences. A broad adverse-event definition also includes events that may not be related to treatment. The registry explicitly states that an adverse event need not have a causal relationship with the administered treatment. Thus, the count should not be read as a count of events caused by REL-1017.

In general, over-dispersion matters when event data vary more than a statistical model expects. It can make standard errors too small if a model assumes less variability than the data contain. This is a general concept and is not a reported feature or analysis of this trial. The posted primary outcome is a participant count, and the registry record does not report an over-dispersion assessment or model for it.

How should planning illustrations be read?

General sample-size planning asks how much information a study may need to detect an effect under stated assumptions. The registry's planning description says its illustrations use an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial's own design justification. The illustrations are not observed power and do not establish that the trial was adequately powered for the primary safety outcome. The registry record does not report the protocol's sample-size justification.

The registry record also does not report a statistical analysis plan for the primary endpoint, the handling of missing data, or a model for the event counts. Without those details and a defined comparison, the available numbers are best interpreted as descriptive safety results. They document counts in the stated arms and timeframe; they do not constitute a complete estimate of treatment differences or their precision.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures and 16 analyses. The secondary outcomes include measures of depression symptoms, clinical severity, suicide severity, and ECG parameters. Some outcome names appear more than once in the registry list. The record does not explain whether repeated entries represent different time points, analyses, or other distinctions. For the primary outcome, the registry says that it has several categories or time points and was not reduced to one comparison.

When several outcomes, time points, or treatment contrasts are tested, multiplicity can increase the chance of a positive result arising by chance. In general, a prespecified testing hierarchy or adjustment can control this risk, while exploratory analyses may be interpreted more cautiously. The multiplicity strategy for this study is not reported in the registry record. No adjustment or unadjusted primary-outcome test should be inferred from the descriptive counts.

The record identifies a safety population: all randomized patients who received any study treatment. It does not state the analysis population used for the secondary outcomes or provide a separate intention-to-treat definition. The approach to missing outcome data, withdrawals, incomplete assessments, and treatment discontinuation is not reported in the registry record. These details matter because missing observations can affect which participants contribute to an analysis and how group comparisons are interpreted.

The record does not describe a statistical analysis plan, methods for handling multiple comparisons, or prespecified rules for selecting among categories and time points. The listed counts can be reported descriptively, but the absence of those methods limits interpretation of inferential claims.

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 registry lists serious adverse event counts of 0 in the REL-1017 25 mg arm, 0 in the REL-1017 50 mg arm, and 0 in the placebo arm. The numbers at risk for these results are 19, 21, and 22, respectively. Death counts are also listed as 0 for each arm. No serious adverse event terms are listed in the record.

For other adverse events, the numbers of affected participants are 9 in the REL-1017 25 mg arm, 15 in the REL-1017 50 mg arm, and 12 in the placebo arm. Those counts describe participants, not event episodes. They do not identify the event types, severity, duration, or assessed relationship to treatment. The registry's broad definition makes clear that an adverse event is not necessarily caused by the study treatment.

Zero recorded serious events in these groups is a description of the posted results, not proof that serious events cannot occur. Similarly, the other-event counts alone do not establish a difference in risk between arms. The registry does not report a statistical comparison or uncertainty interval for these safety outcomes. The stated safety population includes randomized patients who received any study treatment, and the event assessment timeframe is 21 days.

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

The posted results document safety-event counts for a randomized, placebo-controlled Phase 2a study of adjunctive REL-1017 in adults with major depressive disorder. They show zero recorded serious adverse events and zero deaths in each arm, alongside the reported counts of participants affected by other adverse events. These findings describe the registry's recorded outcomes within the specified safety population and assessment period.

They do not establish that REL-1017 is safe or unsafe, or that it changes the risk of adverse events relative to placebo. The record does not provide a single primary-outcome comparison, an effect estimate, a confidence interval, or a statistical test. Raw counts are not sufficient to determine the precision or statistical significance of a group difference. The record also does not report event-level detail that would show the types, severity, or treatment relationship of the events.

The study's stated aims also included pharmacokinetic profile and symptom response, and secondary outcomes included depression symptom and severity measures. Those outcomes are distinct from the primary safety endpoint. Numerical findings for them are not reported in the registry record, so the adverse-event counts do not establish whether symptom scores changed or whether any change differed between groups.

The study was short in its dosing schedule, with treatment over 7 days, while the primary safety outcome used a 21-day timeframe. These registry entries define the setting to which the counts apply. They do not determine what might occur over a longer treatment period or in populations not described by the study summary.

The statistical meaning is therefore limited but useful: the record identifies what was counted, in which arms, and over what timeframe, while leaving important comparative and event-level questions unanswered. Interpretation should remain descriptive unless a fuller analysis with defined comparisons and uncertainty estimates is available.

13. Why This Trial Matters Statistically

This trial is statistically informative because its primary endpoint is a safety count rather than a continuous symptom score. A count of participants affected can be straightforward to communicate, but it has limited interpretive reach unless the event definition, time window, population, group denominators, and comparison are all clear. The registry specifies these core elements, allowing the posted figures to be read in context rather than as free-standing counts.

The three-arm structure also makes the choice of comparison important. The two REL-1017 dose arms and the placebo arm permit different questions, such as comparing each dose with placebo or comparing the doses with one another. Those questions are not interchangeable. The registry does not report a single primary contrast for the endpoint, so the counts should not be treated as a definitive comparison among treatments.

The record illustrates the difference between a descriptive result and an inferential conclusion. Counts show how many participants were recorded as affected; an effect estimate and an uncertainty interval would help assess the size and precision of a treatment contrast. Neither is reported for the primary outcome. This distinction is particularly relevant when event counts are modest and group sizes differ, because a numerical ordering of counts does not by itself establish a meaningful or statistically reliable difference.

Finally, the registry links a brief dosing period to a longer adverse-event assessment timeframe and defines adverse events broadly, including events not necessarily caused by treatment. That makes careful interpretation of endpoint scope essential. The results are relevant as a record of observed safety events under the study's stated conditions, but they do not answer every question about causality, event type, or longer-term experience.

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 main limitation for interpreting the primary outcome is that the registry does not report a single treatment contrast, effect estimate, confidence interval, or statistical test. It explicitly indicates that the primary outcome has several categories or time points and was not reduced to one comparison. The descriptive counts therefore cannot be translated into a precise comparative estimate from the registry record.

The adverse-event outcome is broad, and the available results do not provide event-level descriptions. The record does not report the types, severity, duration, recurrence, or assessed treatment relationship of the other adverse events. It also does not provide a breakdown by visit or time point. Although the record lists no serious adverse event terms and reports zero serious events per arm, the available summary does not explain how event coding or adjudication was performed.

The analysis methods are incompletely described. The record does not report the statistical analysis plan, missing-data handling, the method used for any primary comparison, or an approach to multiplicity. It identifies the safety population but does not provide the analysis populations for the other outcomes. It also does not explain the registry's triple-masking label alongside the double-blind wording in the official title.

The study summary describes adults with a current major depressive episode and an inadequate response to 1 to 3 antidepressant courses, but the background antidepressant is not identified. The registry describes both in-patient and out-patient periods without reporting their timing or duration. These omissions limit detail about treatment context and assessment conditions. The posted safety counts apply to the defined study setting and timeframe; broader claims about other populations or longer exposure are not supported by this record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD — NCT03051256.
• Registry record last updated 2023-11-01; status last verified 2023-10.
• Results first posted 2021-03-17.
• 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.

18. Record Summary

The registry record describes NCT03051256 as a completed Phase 2a, multicenter, randomized, parallel-group study of adjunctive REL-1017 in adults with major depressive disorder. It lists three arms: REL-1017 25 mg, REL-1017 50 mg, and placebo. Enrollment is listed as 62. The recorded start date is 2018-05-11, and the primary completion date is 2019-07-30.

The primary outcome is the incidence of treatment-emergent adverse events, measured as the number of participants affected over 21 days. The safety population is described as randomized participants who received any study treatment. Posted results list zero serious adverse events and zero deaths in each arm; other adverse-event participant counts are 9, 15, and 12, respectively. The registry does not report a single comparative analysis or uncertainty estimate for the primary endpoint.