Ketamine for Relapse Prevention in Recurrent Depressive Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ketamine for Relapse Prevention in Recurrent Depressive Disorder (NCT02661061), a randomized phase 1 study. The primary outcome is Completion Rate for Randomised Treatment Phase.

2. Clinical Question

The trial was a randomised, controlled, parallel-group pilot. Its stated purpose was to assess trial processes and help inform a future definitive trial. Relapse prevention was the clinical context for the comparison, but the primary outcome focused on whether participants completed the randomised treatment phase rather than on a measure of clinical benefit.

The record lists a secondary outcome of depression relapse rate during treatment and follow-up. However, the posted primary results concern completion counts. They do not establish whether either intervention changes relapse risk or other clinical outcomes.

3. Trial Design

KINDRED was a phase 1, randomised, controlled, parallel-group pilot trial sponsored by St Patrick's Hospital, Ireland. The registry describes quadruple masking, but does not report which groups of people were masked or how masking was maintained. The design allocated participants to ketamine or midazolam; the record does not report the allocation sequence method or allocation concealment procedures.

The record gives an enrollment of 9. The posted primary outcome counts are 3 of 5 in the ketamine group and 2 of 4 in the midazolam group. The stated primary analysis population was all randomised participants who received one infusion, described in the record as intention to treat. The record does not provide further detail on the handling of participants who did not receive an infusion.

Participants assigned to ketamine were to receive four two-weekly infusions at 0.05mg/kg. Those assigned to midazolam were to receive four two-weekly infusions at 0.045mg/kg. Both arm descriptions state that a consultant anaesthetist administered all infusions.

The registry lists a start date of 2015-12 and a primary completion date of 2018-05-23. The study status is terminated. The reason for termination and the date it occurred are not reported in the registry record. The brief description says the pilot was intended to assess trial processes, primarily recruitment and retention, to inform a future definitive trial. Further details of the protocol, recruitment procedures, and operational criteria for completion 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.

Before assignment: Participants were randomised from n=28 participants in an observational phase, all of whom were receiving inpatient treatment for recurrent depressive disorder. Participants were monitored weekly for response to treatment and those who responded were invited to be randomised.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomised participants who received one infusion were analysed (intention to treat)

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 Completion Rate for Randomised Treatment Phase, measured over 2 years.

The primary endpoint was the completion rate for the randomised treatment phase, with the outcome recorded as a count of participants. The record describes this as the primary process outcome because the pilot’s main purpose was to assess trial processes, especially recruitment and retention, and to inform a future definitive trial. It explicitly states that the study was not designed to assess efficacy.

A completion count answers an operational question: how many participants in the stated analysis population completed the randomised treatment phase? The posted results report 3 of 5 participants in the ketamine group and 2 of 4 in the midazolam group. They do not include a posted estimate of the difference between groups or an uncertainty interval for that comparison.

Completion is distinct from symptom improvement, relapse prevention, or other clinical benefit. The registry also lists depression relapse rate during treatment and follow-up as a secondary outcome, but the primary endpoint should be interpreted as a measure of trial participation and retention through treatment. The precise completion criteria and the treatment-phase timeframe for this endpoint are not reported in the registry record; the outcome timeframe is listed as 2 years.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either completed the randomised treatment phase or did not. The registry expresses the primary result as a count of participants rather than as a continuous measurement. It reports 3 of 5 for ketamine and 2 of 4 for midazolam. These counts are the posted outcome data; no adjusted or unadjusted comparative estimate is reported.

What does a binary outcome comparison estimate?

In general, a comparison of two groups on a binary outcome can be expressed in several ways. It might estimate a difference in the proportions experiencing the outcome, a ratio of those proportions, or an odds-based measure. Each describes a different scale of comparison. The measure used should be specified in the analysis plan, and its interpretation depends on the outcome definition and the analysis population. The registry record does not report a selected comparative measure or an analysis method for this endpoint.

The record indicates that values were missing or not estimable for a two-arm comparison of this binary endpoint. It reports no analyses. As a result, the posted completion counts can be described, but a comparative effect and its uncertainty cannot be recovered from the registry results. No p-value or confidence interval for a between-group comparison is reported.

Why does the small count matter?

As a general statistical matter, estimates based on sparse binary outcomes are often imprecise. A small change in the observed count can have a noticeable effect on an estimated group proportion or comparison. Confidence intervals communicate this uncertainty by showing a range of values compatible with the observed data under a stated method. For sparse data, the choice of method can matter, and some standard approximations may be unreliable. The registry does not report a method, interval, or comparison for the completion outcome, so no specific inferential result should be inferred.

Randomisation is intended, in general, to support a fair comparison by assigning participants to groups through a chance process. The record identifies the trial as randomised, but does not report details of sequence generation or allocation concealment. The record also identifies quadruple masking without specifying which participants or study personnel were masked. Those labels describe design features, but the available registry information does not permit a fuller assessment of how these procedures were implemented.

What does the planning illustration represent?

The record describes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses a total event count; for other outcomes, it gives participants per arm. The actual planning values are not reported in the registry record. Such values are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect.

In general, a sample-size calculation depends on assumptions about the effect to detect, variability or event frequency, significance level, allocation, and analysis method. A planning exercise based on an observed effect can be especially uncertain when that effect comes from a small pilot. The planning illustration does not replace a prospectively justified design for a future trial; the registry record does not report a sample-size justification or statistical plan.

How should statistical significance be understood?

In general, a p-value measures how incompatible the observed data are with a specified statistical model under a null hypothesis. It does not measure the probability that a treatment works, nor does it describe the size or importance of an effect. A confidence interval is useful alongside an estimate because it conveys precision and a range of plausible values under the method. Neither is reported for this primary comparison. With no posted test or estimate, statistical significance cannot be evaluated from the registry record.

More broadly, the record supports a descriptive reading of the observed completion counts and identifies important limits on interpretation. The endpoint is a participant count for a process outcome; the study is described as a pilot not designed to assess efficacy; and a two-arm comparison is not reported as estimable. Those features should guide any statistical interpretation of the posted results.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Ketamine", "Midazolam")
n      <- c(5, 4)
events <- c(3, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Ketamine  5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2
ARM  Midazolam  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one secondary outcome: depression relapse rate during treatment and follow-up. It reports two outcome measures and no analyses. No secondary-outcome result or statistical comparison is posted. The record does not report whether the secondary outcome was analysed, how it was defined, or whether any adjustment for multiple testing was planned.

In general, testing multiple outcomes can increase the chance of finding an apparently notable result by chance if each is assessed independently without an appropriate plan. A prespecified analysis strategy can clarify which outcomes are primary, how secondary outcomes will be interpreted, and whether multiplicity adjustments are needed. The statistical plan and any multiplicity approach are not reported in the registry record. Because no secondary analysis is posted, there is no basis to infer a result for relapse rate from the primary completion counts.

The primary analysis population is described as all randomised participants who received one infusion, with the record using the label intention to treat. That wording identifies a restriction based on receiving an infusion; the record does not explain how randomised participants who received no infusion were handled. It does not report whether every eligible participant had complete outcome data, how missing endpoint data were handled, or whether any imputation or sensitivity analysis was conducted. The extent and pattern of missing data are not reported in the registry record.

These omissions matter because analysis populations and missing-data procedures can affect estimates and their interpretation. In general, an intention-to-treat approach and a per-protocol approach answer different questions, and missing outcomes can introduce uncertainty or bias if their occurrence is related to participant characteristics or outcomes. The registry’s population description should be quoted as written rather than expanded into an assumed analysis procedure. No detailed statistical analysis plan is reported in the registry record.

12. 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 reports serious adverse events for 0 of 5 participants in the ketamine group and 0 of 4 in the midazolam group. Deaths are reported as 0 in each group. Other adverse events are reported for 1 of 5 participants in the ketamine group and 1 of 4 in the midazolam group. These are counts among the participants listed as at risk in each group.

Serious adverse events and other adverse events are separate categories in the registry results. The record lists no serious adverse-event terms, so it does not provide descriptions of serious events. It also does not provide the nature, timing, severity, or relationship to study intervention of the other adverse events in the posted figures.

As a general point, a zero count in a small group does not establish that an event cannot occur; it describes what was reported in the observed group. These safety counts are descriptive and do not establish comparative safety. The small groups and the lack of event detail limit interpretation, and the counts should not be taken as a complete assessment of risk.

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

The posted results mean that the registry reports treatment-phase completion counts of 3 of 5 for ketamine and 2 of 4 for midazolam. The trial was a pilot focused on processes such as recruitment and retention. These observations can inform understanding of how participants progressed through the randomised treatment phase in this study, but they are not a definitive estimate of completion in a broader population.

The result does not show that one intervention is more effective than the other. Completion is not the same as symptom response or relapse prevention, and the registry states that the study was not designed to assess efficacy. Although depression relapse rate during treatment and follow-up is listed as a secondary outcome, no analysis of it is posted. No between-group comparison for the primary outcome is reported as estimable.

The counts also do not establish that the groups are equivalent. Without a reported comparison estimate and uncertainty interval, the size and precision of any difference cannot be assessed. In general, a small pilot can provide useful process information while remaining unable to support precise clinical conclusions. The registry does not report a formal statistical plan or a sample-size justification that would clarify what clinical effects the study was intended to detect.

The study is marked terminated, but the reason is not reported in the registry record. The status does not, by itself, show whether termination was related to recruitment, retention, safety, funding, or another issue. No explanation should be inferred from the status or outcome counts.

The most defensible interpretation is narrow: these are descriptive process results from a randomised pilot, with limited information about comparative uncertainty and no posted efficacy analysis. They can be considered in planning a future definitive study, consistent with the stated purpose of KINDRED, but do not answer whether either intervention prevents relapse.

14. Why This Trial Matters Statistically

This trial matters statistically because it makes the distinction between a pilot’s process objective and a definitive clinical-effect question explicit. Its primary endpoint was completion of the randomised treatment phase, and the registry states that the study was intended to assess trial processes and was not designed to assess efficacy. That distinction helps prevent a process outcome from being mistaken for evidence about relapse prevention.

The posted completion counts are small: 3 of 5 in the ketamine group and 2 of 4 in the midazolam group. A pilot with sparse counts can describe what happened in the study, but it may not provide a stable or precise comparative estimate. Here, the registry does not post an estimable two-arm comparison, a confidence interval, or a p-value. The limits are visible in the reporting rather than something that can be resolved by interpreting the counts more strongly.

The record also illustrates why analysis populations and endpoint definitions matter. It describes an intention-to-treat population as all randomised participants who received one infusion, but does not explain the handling of those who received no infusion or report missing-data procedures. Those details would be important when designing and interpreting a future trial.

Finally, the listed secondary relapse outcome is not accompanied by a posted analysis, and the reason for termination is not reported. Recognising what is absent is part of sound statistical interpretation. The registry provides a starting point for understanding trial conduct, while leaving important questions about analysis and clinical outcomes unanswered.

15. 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.

This trial has several limitations specific to interpreting its registry record. The primary endpoint is a process measure, treatment-phase completion, and the study is explicitly described as not designed to assess efficacy. It therefore cannot provide a definitive answer about relapse prevention. The posted completion counts are small, and the registry does not report an estimable two-arm comparison or uncertainty interval for this binary outcome.

The record lists depression relapse rate during treatment and follow-up as a secondary outcome but posts no analysis. It does not provide a detailed definition of relapse, assessment schedule, or results for that outcome. The status is terminated, but the reason for termination is not reported in the registry record. The record also does not explain whether the termination affected follow-up or outcome collection.

The stated analysis population includes randomised participants who received one infusion, despite being labelled intention to treat. The handling of randomised participants who received no infusion is not reported. Nor are the amount and pattern of missing outcome data, missing-data methods, or sensitivity analyses reported. These gaps make it difficult to evaluate how the analysis population relates to all randomised participants.

Further statistical details are not reported in the registry record, including the analysis method, comparative effect measure, confidence interval, p-value, sample-size justification, and full statistical analysis plan. The masking label is present, but the roles masked and implementation details are not described. The reason for termination and the nature of the reported other adverse events are also not specified. These limitations call for a descriptive reading of the posted counts rather than an expansive clinical interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ketamine for Relapse Prevention in Recurrent Depressive Disorder — NCT02661061.
• Registry record last updated 2020-01-13; status last verified 2020-01.
• Results first posted 2020-01-13.
• 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.

19. Record Summary

KINDRED was a phase 1, randomised, controlled, parallel-group pilot sponsored by St Patrick's Hospital, Ireland. It compared four two-weekly infusions of ketamine at 0.05mg/kg with four two-weekly infusions of midazolam at 0.045mg/kg. The primary outcome was completion of the randomised treatment phase, a process measure; the record states that the study was not designed to assess efficacy.

The registry reports completion counts of 3 of 5 for ketamine and 2 of 4 for midazolam. It does not post an estimable two-arm comparison or any analysis. Depression relapse rate during treatment and follow-up is listed as a secondary outcome, without a posted analysis. The study status is terminated, and the reason is not reported in the registry record. The results are best read as descriptive information about a small pilot’s process outcome, not as evidence about comparative clinical effectiveness.