Study of Adjunctive or Monotherapy Rapastinel Treatment in Patients With Major Depressive Disorder (MDD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Adjunctive or Monotherapy Rapastinel Treatment in Patients With Major Depressive Disorder (MDD) (NCT03668600), a na phase 3 study. The primary outcome is Count of Participants Experiencing One or More Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a phase 3, multicenter, open-label, long-term extended-access protocol of rapastinel for adults with MDD. The study used a single-group model, with no masking and no randomized allocation. The registry record lists an enrollment of 230 and the status as terminated. The listed start date is 2018-08-23, and the primary completion date is 2019-07-03.

Participants received rapastinel 450 mg by intravenous administration. The arm description specifies weekly or biweekly treatment, or intervals of up to 4 weeks, at the investigator's discretion. The record does not describe how dosing intervals were selected in practice, how long each participant was treated, or whether participants could change schedules over time. The primary endpoint timeframe is up to 45 weeks.

An open-label extended-access protocol answers a descriptive safety question in people who receive the study drug; it is not a controlled efficacy comparison. Because there is no concurrent control arm, observed events cannot be compared within this study against outcomes under a different assigned treatment. Open-label status also means masking was not used, although the registry record does not detail how that status affected event assessment.

The record does not report the protocol's sample-size justification, detailed eligibility criteria, recruitment flow, or reasons for termination. It also does not report whether any interim analyses or protocol amendments occurred. Those omissions limit reconstruction of the planned conduct and of how the final posted safety counts relate to enrollment and follow-up.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Open-label Safety Population will consist of all participants who signed the RAP-MD-99 ICF and who received at least 1 dose of open-label rapastinel during the OLTP of the protocol.

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: The Open-label Safety Population will consist of all participants who signed the RAP-MD-99 ICF and who received at least 1 dose of open-label rapastinel during the OLTP of the protocol.

6. Primary Endpoint

The registry lists the primary outcome as Count of Participants Experiencing One or More Treatment Emergent Adverse Events (TEAEs), measured over Up to 45 Weeks.

The primary endpoint is the count of participants experiencing one or more treatment-emergent adverse events during follow-up of up to 45 weeks. It is a participant-level binary outcome: each person either had at least one qualifying event or did not. The endpoint counts people, rather than counting the total number of events, so multiple events in one participant would still meet the endpoint once.

The registry defines a TEAE as an unfavorable and unintended sign, symptom, or disease associated with use of the study drug, whether or not the event was considered related to the drug. It separately describes an adverse drug reaction as a harmful, unintended reaction incurred during routine administration or use for which a causal relationship with the drug cannot be excluded. This distinction matters: the TEAE definition does not require investigators to judge that the drug caused the event.

Counting participants with any TEAE is a way to describe how commonly participants experienced at least one event during the specified observation period. It does not convey the number, severity, duration, or clinical importance of all events by itself. The registry record does not report the primary endpoint count, so the endpoint's observed frequency cannot be described from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count capture?

The primary outcome is a binary participant-level measure: whether a participant experienced one or more TEAEs. In general, binary outcomes classify each participant into one of two states for the outcome definition. A count of participants with an event is distinct from a count of all event episodes. The former indicates how many people met the definition; it does not show whether one person had a single event or several.

The registry record specifies an endpoint timeframe of up to 45 weeks. In general, an event count is interpretable only alongside its population and observation period. Participants followed for different lengths of time may have different opportunities for an event to be observed. The record does not provide participant-level follow-up duration or a rate adjusted for time at risk, so a time-adjusted interpretation is not available.

How should a single-group safety result be read?

In general, a single-group study can describe the events observed among participants receiving the study intervention. It cannot, by itself, estimate the difference between outcomes under the intervention and outcomes under a comparator. A randomized comparator can help distinguish treatment-group differences from background variation, while this study has no randomized comparison. The listed counts therefore describe this study population and observation, rather than a comparative treatment effect.

Open-label status means treatment assignment was not masked. In general, knowledge of treatment can affect reporting, recognition, or assessment of events, depending on the procedures used. The registry record does not describe event-adjudication procedures or report whether assessors were independent. No conclusion about the direction or size of any such influence can be drawn from the record.

What would uncertainty estimates add?

In general, a confidence interval gives a range of values compatible with an estimate under a specified statistical method and assumptions. It helps readers judge precision: a point estimate alone does not show how much uncertainty surrounds it. A p-value, when used appropriately, addresses compatibility with a specified null model; it is not the probability that a treatment works or that a result is true. Neither a confidence interval nor a p-value for the primary endpoint is reported in the registry record.

Because the primary outcome is binary, one possible descriptive summary would be the proportion of the defined safety population meeting the endpoint, accompanied by an uncertainty interval. That is a general description of an approach, not a result reported for this study. The record gives neither the primary endpoint count nor the endpoint-specific population size needed to reproduce that summary. No recalculated estimate is available from the posted information.

What is the role of sample-size planning?

In general, sample-size planning estimates how many participants a future study may need for a chosen design, outcome, effect size, and statistical operating characteristics. Such planning is not an observed result and does not establish that a completed study had a particular probability of detecting an effect. A planning calculation based on an observed effect is especially dependent on that estimate and on the assumptions used to translate it into a future design.

The planning description associated with this record refers to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with planning for stated fractions of an observed effect. It also distinguishes total event counts for time-to-event outcomes from participants per arm for other outcomes. These are generic planning assumptions, not a description of this trial's single-group design. The record does not report a trial-specific sample-size justification, an observed effect for this endpoint, or resulting planning counts. Such calculations should not be interpreted as observed power for this study.

Why do event definitions and denominators matter?

The primary endpoint includes TEAEs whether or not they were considered related to study drug. This broad definition is useful for describing events occurring during treatment, but it does not assign causation. The separate adverse drug reaction definition requires that a causal relationship cannot be excluded. In general, these categories answer different questions and should not be treated as interchangeable.

Denominators also matter. The record lists enrollment as 230 and uses 230 as the at-risk count for both serious and other adverse-event groupings. The primary endpoint's safety-population definition is based on consent and receipt of at least one dose. The record does not state whether the endpoint population exactly matches the adverse-event denominator, so the measures should not be presumed to share an identical analysis population.

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("Rapastinel")
n      <- c(230)
events <- c(100)
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  Rapastinel  230  100  43.5  37.0  50.2  37.2  49.9  37.2  49.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome measure and no analyses. It does not report a multiplicity strategy, such as adjustment for testing several outcomes or several treatment comparisons. With no posted inferential analyses, there are no reported hypothesis tests to evaluate for multiplicity. The absence of a reported adjustment does not establish that no additional analyses were planned or conducted; those details are not reported in the registry record.

The primary endpoint population is defined as participants who signed the RAP-MD-99 informed consent form and received at least one dose of open-label rapastinel during the open-label treatment period. The record does not report how many participants met this definition, how many were excluded from that population, or how missing endpoint observations were handled. It does not describe imputation, censoring, sensitivity analyses, or rules for incomplete follow-up. These details are important because an endpoint count and its denominator can be affected by who was observed and how incomplete data were treated.

Enrollment is listed as 230, but the record does not give a participant flow showing how enrollment relates to treatment initiation, follow-up, or the endpoint population. It also does not state whether all participants had the same observation duration. Consequently, the extent and potential impact of missing outcome information cannot be assessed from the registry record.

In general, multiplicity concerns arise when several hypotheses or endpoints are examined, because repeated testing can raise the chance of at least one apparently unusual result. Missing-data methods address the fact that outcomes are unavailable for some participants and may affect estimates if the missingness is related to participant characteristics or outcomes. These are general statistical considerations; the record does not report enough detail to determine how either issue was handled in this study.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abortion spontaneous (0.5%), ventricular tachycardia (0.4%), device malfunction (0.4%), pericardial effusion (0.4%), pneumonia (0.4%).

The posted safety figures list 4 of 230 participants with serious adverse events and 14 of 230 with other adverse events; the death count is 0. These are descriptive counts, not comparisons with another group. Seriousness and relatedness are separate concepts: a serious event is not automatically an event caused by the study drug. The registry record's primary TEAE definition likewise includes events whether or not they were considered related to study drug.

The record lists six serious-event terms with percentages: Abortion spontaneous at 0.5%, and Ventricular tachycardia, Device malfunction, Pericardial effusion, Pneumonia, and Rib fracture at 0.4% each. The entries do not report the full event narratives, timing, duration, recurrence, or individual assessments of relationship to treatment. The percentages should therefore be read as registry-listed values attached to those terms, not as evidence of causation.

These figures do not replace the primary endpoint result, which is not reported. They also do not establish comparative risk: there is no control group, and the record does not provide an adjusted analysis or uncertainty estimates. The counts describe what the registry lists for this treated group and should not be generalized beyond that description without further evidence.

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

The record documents an open-label, single-group extended-access study of rapastinel in adults with MDD and posts selected safety counts. It also defines a primary endpoint based on whether participants experienced one or more TEAEs. However, the primary endpoint's observed count is not reported. As a result, the registry record does not permit a direct description of the frequency of that primary outcome.

The serious and other adverse-event counts and the listed event terms offer limited descriptive information. They do not identify which events were caused by rapastinel, and they do not show how the observed experience compares with an alternative treatment or with no study treatment. A single-group open-label design cannot resolve those comparative questions on its own. The record also lacks detail on follow-up, event assessment, and the endpoint population size, limiting interpretation of how completely the counts capture participants' experience.

These results should not be read as evidence that the treatment is effective or ineffective. The registry record does not report an efficacy endpoint or a statistical analysis of treatment benefit. Nor should the listed safety counts be treated as proof that treatment caused or did not cause particular events. They are observations recorded in a study without a concurrent control group.

In general, clinical interpretation depends on the endpoint definition, observation time, population, completeness of follow-up, and precision of estimates, as well as study design. For this study, the registry record supplies some of those elements but not the primary endpoint result, uncertainty estimates, or detailed analysis methods. The defensible conclusion is therefore narrow: the record describes the protocol and lists safety-event counts, while leaving the primary TEAE result and comparative interpretation unavailable.

14. Why This Trial Matters Statistically

This trial illustrates why study design must be considered before interpreting a numerical safety result. The study is phase 3, but its single-group, open-label structure remains descriptive rather than a randomized comparison. A phase label does not substitute for a control group, an endpoint result, or an analysis that supports comparative inference.

It also highlights the importance of distinguishing a broad treatment-emergent event definition from an adverse drug reaction definition. The primary endpoint includes events regardless of whether they were considered related to treatment, while the separate reaction definition concerns events for which a causal relationship cannot be excluded. Keeping those concepts distinct helps avoid treating every event during treatment as drug-caused.

The endpoint is participant-based, not event-based. That distinction matters because a count of people experiencing at least one event answers a different question from the total number of event episodes or the rate of events over time. A clear denominator and consistent follow-up are essential to interpret such a count; the endpoint-specific population size and follow-up detail are not reported.

Finally, this record demonstrates that a named primary endpoint does not guarantee that its result is posted. The registry contains an endpoint definition and some adverse-event counts, yet no primary outcome count or analysis is reported. Statistical interpretation must remain bounded by what is actually available: a protocol description and limited descriptive safety information, without inferential estimates or comparative conclusions.

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.

Several trial-specific limitations constrain interpretation. The protocol is open label and uses a single-group model, with allocation listed as not applicable. There is no randomized control group to provide a like-for-like comparison. Thus, the posted counts cannot estimate a treatment contrast or separate events associated with treatment from events that could occur for other reasons.

The primary endpoint is defined, but its result is not reported. The record also does not report the number of participants meeting the endpoint-specific safety-population definition, even though enrollment is listed as 230. The relation between that defined population and the adverse-event denominator is not explained. This leaves uncertainty about the population represented by the primary endpoint and the completeness of observation.

The record does not report participant-level follow-up, the number with incomplete observations, missing-data methods, or sensitivity analyses. It does not provide detailed event narratives, timing, recurrence, or adjudication methods for the serious-event terms. No confidence intervals, p-values, or other inferential analyses are reported, and the trial's sample-size justification is not reported in the registry record.

Rapastinel dosing could be weekly, biweekly, or at intervals of up to 4 weeks at the investigator's discretion. Actual dosing patterns are not reported. The record also lists the study as terminated but does not report the reason for termination. These gaps limit assessment of exposure, follow-up, and the context for the posted results. The limitations are specific to the information available in the registry record; they do not establish what may have been reported elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Adjunctive or Monotherapy Rapastinel Treatment in Patients With Major Depressive Disorder (MDD) — NCT03668600.
• Registry record last updated 2020-07-17; status last verified 2020-07.
• Results first posted 2020-07-17.
• 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.

19. Record Summary

This phase 3 study was an open-label, multicenter, single-group extended-access protocol of rapastinel for adults with MDD. Rapastinel was administered intravenously at 450 mg on a weekly or biweekly schedule, or at intervals of up to 4 weeks at the investigator's discretion. The registry record lists enrollment of 230, status as terminated, a start date of 2018-08-23, and a primary completion date of 2019-07-03.

The primary endpoint was the count of participants experiencing one or more TEAEs during follow-up of up to 45 weeks. Its result and any statistical analyses are not reported. Posted safety figures list 4 of 230 participants with serious adverse events, 14 of 230 with other adverse events, and 0 deaths. Because there was no control group, these counts are descriptive and do not establish comparative effects or causation.