A Translational and Neurocomputational Evaluation of a Dopamine Receptor 1 Partial Agonist for Schizophrenia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Translational and Neurocomputational Evaluation of a Dopamine Receptor 1 Partial Agonist for Schizophrenia (NCT04457310), a randomized phase 2 study. The primary outcome is Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 2.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, triple-masked, crossover study sponsored by Yale University. The condition listed was early course schizophrenia spectrum disorder. The registry records enrollment of 112 and study status as completed. The recorded start date was 2021-03-02, and the primary completion date was 2024-03-22.

The intervention conditions were CVL-562 (PF-06412562) at 1 mg, 4 mg, 15 mg, and 25 mg, along with placebo. The descriptions for the intervention groups state that each subject would complete five test visits, receiving a dose or placebo at each visit. Participants were randomized to the order of the five conditions. This repeated-exposure structure is central to interpreting the design: a dose condition is not the same thing as a separately randomized parallel group.

Triple masking indicates that the registry labels the study as triple-masked, but the record does not identify the masked roles or explain how masking was maintained. The interval between sessions, any washout procedure, and procedures for managing period or sequence effects are not reported in the registry record.

The primary assessment was collected during functional magnetic resonance imaging sessions, with a stated timeframe of up to two hours for each session. The description specifies five fMRI sessions, one at each dose, while the intervention descriptions include placebo among the five visit conditions. Those descriptions do not resolve this wording difference. The statistical analysis plan, including how the crossover observations were modeled, is 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: Data for participants who started test visits at Columbia was required to be removed due to research restrictions per the NIH (see GCE). Secondary outcome results unavailable due to ongoing restrictions per the NIH.

Overall Study

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: Baseline characteristics are provided for the 84 participants with available data.

6. Primary Endpoint

The registry lists the primary outcome as Neural Activity Across Brain Regions During a Spatial Working Memory (sWM) Task- Condition 2, measured over Up to two hours for each fMRI session.

The primary outcome is mean neural activity across brain regions during Condition 2 of a spatial working memory task. It is measured as percentage signal change in blood oxygen level dependent signal during functional magnetic resonance imaging. The specified timeframe is up to two hours for each fMRI session.

Spatial working memory involves keeping a location in mind over a short period. The task description distinguishes the working-memory condition from a motor response without working memory, and from working-memory conditions with a distractor near or far from the original memory location. Condition 2 is described as a motor response without spatial working memory. The registry’s primary outcome title identifies Condition 2, although the record does not spell out this label in the title itself.

As a general statistical point, an imaging measure can serve as a biological or neural target-engagement measure: it evaluates a physiological signal associated with a task, rather than directly measuring everyday functioning. The study’s stated aim is to examine working memory neural circuits and develop imaging biomarkers related to the D1R/D5R target. That aim explains the endpoint’s mechanistic focus, but does not make the imaging measure a direct measure of clinical benefit.

The registry identifies the summary measure as a mean with standard deviation as the dispersion measure. It does not report the primary outcome results or a dose-versus-placebo contrast in the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: mean percentage signal change in blood oxygen level dependent signal. The registry specifies a mean and standard deviation. These summaries describe a central value and the spread of observations, but by themselves do not establish whether differences between conditions are statistically distinguishable or clinically meaningful. The record does not include the outcome values or an inferential comparison.

What would a crossover comparison account for?

General statistical explanation: crossover studies collect measurements from the same participants under different conditions. Since measurements from one participant tend to be more alike than measurements from different participants, an analysis can use paired or repeated-measures methods to represent that dependence. A model might also account for visit period or randomized sequence if these are part of the design and analysis plan. The registry record does not report which model was used, how within-participant correlation was handled, or whether period, sequence, or carryover terms were included.

The trial description says participants were randomized to the order of the dose and placebo visits. Randomizing order can help balance systematic differences in when a condition is received, but it does not by itself show how the final analysis handled visit order. The registry record does not report the randomization implementation, allocation concealment details, or a statistical analysis plan.

How should uncertainty be read?

General statistical explanation: a confidence interval describes a range of values compatible with the data and the assumptions of the analysis, at the stated confidence level. Its width reflects precision: a narrower interval indicates a more precise estimate under those assumptions. A p-value addresses how compatible the observed data are with a specified null model; it is not the probability that a treatment works or that the null hypothesis is true. Neither confidence intervals nor p-values for the primary comparison are reported in the record.

The registry’s stated summary measure is a mean, with standard deviation as the dispersion measure. Standard deviation describes variation among observed values; it is not the same as the uncertainty around a mean or treatment contrast. General statistical explanation: standard errors or confidence intervals are used to describe uncertainty in estimates, and in a crossover design their calculation should reflect repeated observations from the same participant. The required estimates and analysis details are not reported in the registry record.

What do the planning illustrations represent?

The record describes sample-size planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is expressed as a stated fraction of the observed effect. These are planning illustrations, not observed power and not a substitute for an estimate and uncertainty interval from the trial. The record’s primary outcome is not reduced to one comparison, so interpretation of any illustration depends on the comparison and effect used for planning. The illustrations do not establish that the trial was adequately powered for every dose, outcome category, or analysis.

General statistical explanation: over-dispersion occurs when outcomes vary more than a statistical model expects. It can make standard errors too small if ignored. The primary endpoint is a continuous imaging measure, and the registry does not report an over-dispersion assessment or indicate that this issue arose. More broadly, the statistical model and diagnostics are not reported in the registry record, so the assumptions used for inference cannot be evaluated.

The registry identifies 10 outcome measures and 0 analyses. The number of outcomes signals that several measures were registered, but it does not tell which were analyzed, how the primary comparison was selected, or whether the reported outcome set was complete. The registry record does not report analysis code, model diagnostics, or the handling of deviations from assumptions. Those omissions limit independent evaluation of the inferential methods.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome with several categories or time points and indicates that it was not reduced to one comparison. It also lists secondary outcomes concerning spatial working memory performance, associations between neural activity and task performance, functional connectivity, resting-state connectivity, change in blood oxygen level dependent signal, and similarity with transcriptomic maps. The record lists 10 outcome measures and 0 analyses.

When multiple outcomes, conditions, time points, or dose comparisons are considered, the chance of obtaining an apparently notable result somewhere among them can increase. General statistical explanation: multiplicity procedures can control error rates across a defined family of comparisons, but the appropriate approach depends on which hypotheses were planned and how they relate. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified family of tests. It is therefore not possible to determine how multiple comparisons were handled.

The analysis populations are not reported in the registry record. The information does not identify how many participants contributed primary endpoint data, how missing imaging observations were handled, or whether analyses followed an intention-to-treat, per-protocol, or other definition. The reasons for missing observations and the extent of missingness are also not reported in the registry record.

General statistical explanation: missing data can affect estimates when the chance of a measurement being absent is related to participant characteristics or outcomes. In repeated-measures studies, missing visits can also leave some participants with incomplete condition sequences. Methods such as likelihood-based repeated-measures models or imputation can address missing observations under specified assumptions, but the assumptions and method need to be reported to assess their credibility. No missing-data approach is reported in the registry record.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: worsening pyschosis (1.2%), fall and loss of vision in eye (1.2%).

The registry reports serious adverse events and other adverse events by intervention condition. For each listed group, the number at risk is 84. Serious events were reported for 0 participants at 1 mg, 0 at 4 mg, 1 at 15 mg, 0 at 25 mg, and 0 for placebo. The record also lists 1 serious event in the category labeled adverse event prior to starting intervention. Deaths are listed as 0 in each group.

For other adverse events, the counts affected were 20 at 1 mg, 21 at 4 mg, 29 at 15 mg, 35 at 25 mg, and 24 for placebo; 0 were listed in the prior-to-starting-intervention category. The serious event terms listed are “worsening pyschosis” and “fall and loss of vision in eye,” each reported as 1.2%.

These are descriptive counts, not estimates of comparative risk. The crossover design means participants may appear under more than one intervention condition, so the at-risk figures should not be added to obtain a number of unique participants. The registry record does not report an inferential comparison of adverse-event rates or explain the population definition used for these summaries. Counts alone do not establish that an event was caused by an intervention.

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

The registry record describes a mechanistic Phase 2 study of CVL-562 in people with early course schizophrenia spectrum disorder. Its primary endpoint is neural activity measured during a spatial working memory task, using blood oxygen level dependent signal in functional magnetic resonance imaging. The study aim is to evaluate working memory neural circuits and develop imaging biomarkers related to D1R/D5R target engagement.

That focus matters for interpreting what the outcome can represent. General statistical and scientific context: a change in an imaging signal can provide evidence about a measured neural process under the study conditions. It does not, on its own, establish improvement in symptoms, everyday functioning, or another patient-centered outcome. The registry lists secondary measures of task performance and brain connectivity, but the results for these measures are not reported in the record.

The posted record does not provide a single primary comparison or numerical primary outcome result. It therefore does not show the estimated magnitude or direction of a dose-versus-placebo difference, nor its precision. No conclusion about whether an observed difference is compatible with a small or large effect can be drawn without an estimate and an uncertainty measure. The absence of a reported result should not be interpreted as a finding of no effect.

The safety counts provide a descriptive account of events by condition, but they do not determine causation or establish comparative safety. Interpretation is further limited because the registry does not report the analysis populations, missing-data methods, statistical model, or multiplicity approach. The record does not report the protocol details needed to assess visit spacing, washout, or the handling of possible period and carryover effects.

Accordingly, the registry supports a description of the design and intended biological measurement, plus the listed adverse-event counts. It does not provide enough statistical outcome information to characterize an efficacy estimate or its uncertainty.

13. Why This Trial Matters Statistically

This trial illustrates a common distinction in clinical research between measuring a proposed biological mechanism and measuring a direct clinical outcome. The registered primary endpoint is a task-based imaging signal. The stated scientific aim is to examine working memory circuits and establish imaging biomarkers related to D1R/D5R target engagement. That makes the outcome relevant to translational research, while also defining the limits of what it can establish about clinical function.

The crossover design is statistically important because the dose and placebo observations are collected across repeated visits within participants. General statistical principle: within-person comparisons can account for stable differences between people, but valid uncertainty estimates need to reflect the dependence among repeated measurements. The registry record does not identify the model used for this purpose, so the statistical treatment of the crossover structure cannot be assessed from the information.

The record also highlights why endpoint definition and multiplicity matter. The primary outcome includes several categories or time points and is not reduced to one comparison, while the registry lists multiple secondary outcomes. Without a specified primary contrast, analysis population, and multiplicity strategy, readers cannot determine which comparison was intended to carry the principal inferential claim.

Finally, registration status and completion status are not substitutes for posted results. The registry marks the study completed, but the information does not include a primary outcome estimate or uncertainty interval. For statistical interpretation, a clearly defined estimand and transparent reporting of estimates, uncertainty, missingness, and analysis methods are essential. Those details would allow readers to distinguish evidence about a neural signal from evidence about broader clinical outcomes.

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.

Several trial-specific details needed to evaluate the design and results are not reported in the registry record. The visit interval, washout procedures, and protections against carryover are not described. These details are relevant in a crossover study because prior conditions or changes over time could influence later measurements.

The record states that there were five test visits and describes randomized ordering of dose and placebo conditions. It also states that there were five fMRI sessions, one at each dose. This wording does not clearly reconcile the listed placebo condition with the description of sessions at each dose. The record does not provide enough detail to resolve that ambiguity.

The primary outcome title identifies Condition 2, while the task description defines four task conditions. The record does not provide the actual primary outcome results, a contrast specification, confidence intervals, or p-values. It also does not report how the multiple task conditions or time points were handled in the analysis.

Participant flow, analysis populations, missing imaging observations, and reasons for missingness are not reported in the information. Neither the statistical model nor its assumptions, multiplicity procedures, or handling of period and sequence effects is reported. These gaps prevent assessment of the primary comparison’s precision and robustness.

The adverse-event summaries are descriptive and list the same at-risk count for each condition. In a crossover study, these condition-specific figures should not be interpreted as separate parallel-arm populations or added to infer unique participants. The registry record does not report an adjusted safety comparison or causal attribution method.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Translational and Neurocomputational Evaluation of a Dopamine Receptor 1 Partial Agonist for Schizophrenia — NCT04457310.
• Registry record last updated 2025-10-15; status last verified 2025-09.
• Results first posted 2025-10-15.
• 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

NCT04457310 is a completed Phase 2 randomized, triple-masked crossover study sponsored by Yale University. It enrolled 112 people with early course schizophrenia spectrum disorder. The study compared CVL-562 (PF-06412562) at 1 mg, 4 mg, 15 mg, and 25 mg with placebo across randomized visit orders.

The primary outcome was mean neural activity during Condition 2 of a spatial working memory task, measured as percentage signal change in blood oxygen level dependent signal during functional magnetic resonance imaging. The registry lists 10 outcome measures and 0 analyses. It does not report a reduced primary comparison or numerical primary result in the record.

Serious and other adverse-event counts are listed by condition, with no deaths reported in the listed groups. The registry record does not report the primary analysis model, analysis populations, missing-data methods, or multiplicity procedures.