Opiate Suicide Study in Patients With Major Depression: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Opiate Suicide Study in Patients With Major Depression (NCT04116528), a randomized phase 3 study. The primary outcome is Change in Scale for Suicidal Ideation (SSI) Total Scores Will be Analyzed as the Primary Outcome Measure Using Mixed Effects Models,.

2. Clinical Question

The study is framed as an exploration of whether ketamine followed by buprenorphine produces more rapid and sustained anti-suicidal effects than ketamine followed by placebo. Statistically, the primary question concerns the pattern of SSI scores over time by treatment group. It is not a comparison of ketamine against placebo, since ketamine preceded both assigned treatments. The registry lists MADRS and HAM-D change scores as secondary outcomes, but the primary outcome is the SSI total score. The registry record does not report the numerical primary outcome results in a form that permits a direct estimate of the treatment-group contrast or its precision.

3. Trial Design

The registry classifies this as a Phase 3, randomized, quadruple-masked, parallel-group study sponsored by Stanford University. The listed enrollment is 50. The recorded start date is 2020-08-01, the primary completion date is 2025-04-28, and the status is completed. The registry does not describe the specific roles covered by quadruple masking, so those roles cannot be identified from the record.

Before the randomized comparison, all participants received an intravenous infusion of ketamine. They were then assigned to buprenorphine or placebo for 4 weeks. The treatment descriptions characterize assignment as random and describe the comparison as double blind, while the registry’s design classification says quadruple masking. The record does not explain the difference between those masking descriptions. The parallel-group design means participants were assigned to one of the comparison groups rather than being described as crossing between both treatments.

The brief summary describes 60 subjects and 60 infusions, with approximately 24 infusions per year, and says the study would take approximately 2.5 years to complete. The enrollment field, by contrast, records 50 participants. The registry record does not explain the difference between the summary’s planned subject count and the enrollment figure. It also does not give a final analyzed-participant count. Enrollment should therefore not be treated as the number included in the primary analysis.

The primary analysis is described as using a modified intention-to-treat population: randomized participants who received one week of treatment and completed the week 1 assessment. The population description also refers to participants with at least one post-ketamine SSI assessment. The number meeting these criteria is not reported in the registry record. The study lists MADRS Change Score and HAM-D Change Score as secondary outcomes.

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.

Before assignment: The study included a sequence in which all subjects received an infusion of ketamine and then were to receive either buprenorphine or placebo. The randomization was done prior to ketamine.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Participants who completed at least 1 week of buprenorphrine or placebo, and completed at least 1 post-ketamine SSI assessment

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.

Population: Participants who completed at least 1 week of buprenorphrine or placebo, and completed at least 1 post-ketamine assessment

6. Primary Endpoint

The registry lists the primary outcome as Change in Scale for Suicidal Ideation (SSI) Total Scores Will be Analyzed as the Primary Outcome Measure Using Mixed Effects Models,, measured over Day 1 and 31.

The primary endpoint is change in total score on the Scale for Suicidal Ideation (SSI). The registry describes the SSI as having 19 items, each scored from 0 to 2, for a maximum total score of 38. Higher scores indicate worse suicidal ideation. A change in total score is intended to capture how the measured level of suicidal ideation varies during the study; it does not, by itself, describe every aspect of a participant’s experience or establish why a score changed.

The registry identifies Day 1 and Day 31 as the primary outcome timeframe and says measurements were modeled across study days 1, 3, 10, 17, 24, and 31. Using repeated scores can represent both the level and pattern of change over time, rather than relying only on a single assessment. The planned model included treatment group, time, and a treatment-by-time interaction, so the primary hypothesis concerned whether the trajectory differed between groups.

General: a scale endpoint can provide a consistent numerical measure for comparing groups, but interpretation depends on the scale, timing, analysis population, and uncertainty around the estimated contrast. The registry record does not report a single numerical primary comparison or its confidence interval, so the size and precision of any group difference cannot be described from the recorded outcome information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a linear mixed-effects model for the primary SSI outcome. This approach is designed for data in which the same participants contribute measurements at multiple times. The analysis included random effects for patient and fixed effects for treatment group, time as a continuous variable, and the time-by-treatment group interaction. It also used an unstructured covariance matrix. The record says the primary analysis used a modified intention-to-treat population, defined by treatment exposure and completion of the week 1 assessment.

Why model repeated measurements?

General: measurements from the same participant are usually related. A person’s score at one assessment may be more similar to that person’s other scores than to scores from another participant. A mixed-effects model can represent this participant-level structure while estimating average patterns across treatment groups. It can also use measurements across the scheduled assessment times rather than treating each time point as an unrelated study.

The registry describes patient as a random effect. General: a random effect represents participant-specific variation around the overall pattern, allowing participants to differ in their underlying scores or trajectories. Treatment group is described as a fixed effect, which represents the group comparison of interest. Time is treated as a continuous variable, and the treatment-by-time interaction represents whether the modeled relationship between time and score varies by assigned group. The registry does not report the fitted coefficients, the model’s estimated group trajectories, or a single contrast derived from them.

What does the covariance structure do?

The model used an unstructured covariance matrix. General: a covariance structure specifies how measurements at different times are related in the model. An unstructured choice allows the relationships among repeated observations to be estimated without imposing a particular pattern. This flexibility can be useful when the correlation pattern is not assumed to follow a simpler form, but it also means the model must estimate multiple covariance quantities. The registry does not give the estimated covariance values or additional diagnostics, so the adequacy of the fitted structure cannot be assessed from the record.

What does the SSI score represent?

The SSI contains 19 items scored from 0 to 2, with a maximum total of 38; higher scores indicate worse suicidal ideation. The listed assessment days are 1, 3, 10, 17, 24, and 31. The primary outcome timeframe is described as Day 1 and Day 31, while the analysis description specifies repeated observations across the listed study days. The record does not explain how the Day 1 and Day 31 wording relates to the full repeated-measures model or identify a single reported contrast for those assessments.

General: modeling repeated scores can provide an estimate of change patterns while accounting for dependence within participants. The treatment-by-time interaction is relevant when the question is whether those patterns differ across groups. Interpretation still depends on the model specification, the available observations, and the uncertainty of the estimated effects. A model description alone does not show the observed result or demonstrate that assumptions fit the data.

What do the planning assumptions mean?

The registry describes a sample-size planning illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is framed as a stated fraction of the observed effect. General: planning calculations estimate the number of participants that might be needed under selected assumptions; they are not a measure of how much power the completed study actually had. In particular, a planning illustration should not be interpreted as observed power. The numerical planning results and the effect estimate used for that exercise are not reported in the registry record.

The record identifies one analysis and six outcome measures, but it does not report the full statistical analysis plan, model diagnostics, or a numerical primary result. The absence of those details limits independent assessment of the analysis. The registry also does not report whether the listed model was altered after data collection or how any deviations were handled.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and one analysis. It identifies SSI change as the primary outcome and lists MADRS Change Score and HAM-D Change Score as secondary outcomes. The primary outcome description includes repeated assessment times, but the registry record does not present a single numerical comparison across those times. It does not report a multiplicity adjustment, a testing hierarchy, or how the primary and secondary outcomes were handled together. Therefore, the record does not establish whether or how the chance of false-positive findings across multiple outcomes or time points was addressed.

The modified intention-to-treat population is described as randomized participants who received one week of treatment and completed the week 1 assessment. The population field also refers to participants who completed at least one week of buprenorphine or placebo and completed at least one post-ketamine SSI assessment. These descriptions indicate that inclusion in the stated primary analysis depended on treatment exposure and assessment completion. The number randomized, the number meeting the analysis criteria, and the number with outcome data at each assessment are not reported in the registry record.

Missing-data handling is not reported in the registry record. The record does not specify how incomplete repeated measurements were handled, whether any imputation was used, or what assumptions about missing observations were adopted. Interim analyses and a detailed statistical analysis plan are also not reported. These omissions matter because the analysis population and handling of incomplete observations can affect which participants contribute information and how precisely the treatment comparison is estimated. They do not, by themselves, establish the direction or magnitude of any bias.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry records zero serious adverse events in the buprenorphine-after-ketamine group among 25 participants at risk, and zero in the placebo-after-ketamine group among 25 participants at risk. It records 18 participants with other adverse events in the buprenorphine group and 8 in the placebo group, with 25 participants at risk in each group. Deaths are recorded as zero in both groups. These are counts as recorded, not estimates of a treatment effect.

General: adverse-event counts describe events observed and recorded under the trial’s reporting procedures. They do not by themselves show whether an event was caused by a treatment, how severe non-serious events were, or whether participants experienced more than one event. The registry does not report further definitions, event-level detail, exposure-adjusted analyses, or the statistical comparison for these counts. The serious adverse event term list is empty, so specific serious-event terms are not reported in the registry record. The counts should be interpreted separately from the SSI efficacy outcome and do not establish a benefit or harm comparison.

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

The registry record establishes the question the study was designed to address: whether SSI scores changed differently over time after ketamine in participants assigned to buprenorphine or placebo. It describes random assignment, the treatment period, the outcome scale, and a mixed-effects model. It does not report a single numerical primary comparison or its uncertainty. As a result, the record does not support a conclusion about the direction, magnitude, or precision of the difference in SSI trajectories.

The status is completed, but completion is not a substitute for posted outcome estimates. Nor does the design description establish that one treatment was superior, equivalent, or ineffective. The reported adverse-event counts are not a substitute for the primary outcome and do not establish causality. Any claim about clinical effects would require results and context that are not reported in the registry record.

General: statistical evidence is most informative when an estimate is considered alongside its uncertainty, the analysis population, and the way outcomes and time points were handled. A model can be appropriate in principle and still yield an uncertain estimate; conversely, a model description without results cannot be interpreted as evidence for a particular effect. The registry does not report the primary estimate or confidence interval needed to assess precision.

The record lists enrollment as 50, while the brief summary describes 60 subjects. It does not give the final primary-analysis count. Those figures should not be treated as interchangeable, and the record does not explain their difference. The sample-size discussion is a planning illustration, not observed power. Together, these limits mean that the posted record is informative about design and intended analysis but insufficient for a numerical interpretation of the primary efficacy question.

13. Why This Trial Matters Statistically

This trial raises a statistical question about treatment trajectories rather than only a comparison at one assessment. The registry lists repeated SSI measurements on days 1, 3, 10, 17, 24, and 31 and describes a treatment-by-time interaction in a linear mixed-effects model. That structure connects the analysis to the stated interest in whether effects are more rapid or sustained. Repeated-measures methods can use observations across time while accounting for within-participant dependence, rather than treating all scores as independent.

The record also illustrates why a clear result needs more than a model description. Readers need the estimated treatment contrast, its uncertainty, and an explanation of which analysis population contributed data. Those numerical primary results and the analysis count are not reported in the registry record. The registry lists enrollment as 50 but the brief summary describes 60 subjects, and it does not explain the difference. This makes it especially important not to equate the enrollment figure with the analyzed sample.

General: statistical interpretation depends on matching the analysis to the question and reporting enough detail to evaluate uncertainty. When multiple outcomes or measurement times are involved, reporting the chosen contrast and multiplicity approach helps readers understand what inference is being made. The registry lists six outcome measures and one analysis but does not report a multiplicity strategy. The case therefore highlights both the value of modeling longitudinal outcomes and the importance of complete, interpretable results reporting.

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 principal limitation for interpreting the study’s efficacy question is that the registry record does not report a single numerical primary comparison. The primary outcome is described across several assessment times, and the record indicates that it has not been reduced to one comparison. No primary effect estimate, confidence interval, or p-value is reported in the registry record. Without these results, the magnitude and precision of the between-group SSI comparison cannot be assessed.

The recorded enrollment is 50, while the brief summary refers to 60 subjects. The registry does not explain this difference, report the number randomized, or state how many participants were included in the modified intention-to-treat analysis. The analysis population depends on treatment exposure and assessment completion, but the number of participants satisfying those criteria is not reported.

The record describes repeated-measures modeling but does not report the fitted estimates, model diagnostics, covariance estimates, or sensitivity analyses. It does not report how missing observations were handled, whether multiplicity was addressed, or whether interim analyses occurred. The masking classification also differs between the quadruple-masked design field and the double-blind treatment descriptions; the record does not explain the difference. These limitations restrict assessment of analysis choices and precision. They do not establish that the analysis was inappropriate or that any particular result occurred.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Opiate Suicide Study in Patients With Major Depression — NCT04116528.
• Registry record last updated 2026-05-22; status last verified 2026-04.
• Results first posted 2026-05-22.
• 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

NCT04116528 is listed as a completed Phase 3 randomized parallel-group study sponsored by Stanford University. The registry describes a comparison of buprenorphine and placebo for 4 weeks after an intravenous ketamine infusion received by all participants. The recorded enrollment is 50, while the brief summary describes 60 subjects.

The primary outcome is change in SSI total score, assessed on Day 1 and Day 31 and modeled across study days 1, 3, 10, 17, 24, and 31. The registry describes a linear mixed-effects model and a modified intention-to-treat population. MADRS and HAM-D change scores are listed as secondary outcomes. Numerical primary results, the final analysis count, missing-data procedures, and multiplicity handling are not reported in the registry record. Serious adverse events and deaths are recorded as zero in both groups; other adverse events are recorded for 18 participants in the buprenorphine group and 8 in the placebo group.