D-serine Augmentation of Neuroplasticity: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for D-serine Augmentation of Neuroplasticity (NCT03711500), a randomized phase 1, phase 2 study. The primary outcome is Plasticity Improvement (Change in Tone Matching Threshold).

2. Clinical Question

3. Trial Design

This completed study, NCT03711500, is titled “D-serine Augmentation of Neuroplasticity.” The official title describes D-serine augmentation of neuroplasticity-based auditory learning in schizophrenia. The registry lists schizophrenia and schizoaffective disorder as conditions and Phase 1 and Phase 2 as the study phases. The sponsor is the New York State Psychiatric Institute.

The design is recorded as randomized, triple-masked, and parallel-group. The posted enrollment is 45. The arms listed are D-serine 80 mg/kg, placebo, D-serine 100 mg/kg, and D-serine 120 mg/g. The last dose label is reproduced as recorded; the registry record does not clarify it. Arm descriptions are not reported in the registry record.

The study start date is 2019-03-13, the primary completion date is 2021-04-30, and the status is completed. Participants underwent three treatment sessions, one per week. The primary outcome was assessed at the end of the third session. The record does not provide further details about the schedule of other assessments, the treatment procedures, or the method used to generate or conceal the random allocation.

The registry lists four outcome measures, but does not post secondary outcome results. It includes primary endpoint summaries for the four listed arms, but no two-arm inferential analysis is available. The identity of the parties masked, the protocol’s planned statistical methods, and any sample-size justification 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: randomized

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 Plasticity Improvement (Change in Tone Matching Threshold), measured over At the end of Treatment session 3 (3rd of three sessions).

The primary endpoint is titled “Plasticity Improvement (Change in Tone Matching Threshold).” It is a continuous measure expressed as a log ratio, and the posted group summaries are means with standard deviations. The measure is intended to capture changes in auditory tone discrimination over the treatment sessions.

In the auditory remediation task, a participant hears paired tones and indicates which tone has the higher pitch. The task adjusts the ratio between the tones using a two-down/one-up staircase procedure, aiming to maintain a steady level of performance. Threshold was calculated at the initial plateau, defined in the record as trials 20-30 during treatment session 1, and again at the end of treatment session 3.

Plasticity Improvement is the change from the initial plateau to the end of the third treatment session. Larger, more positive values represent greater improvement in threshold; zero represents no improvement. The values were log transformed. This endpoint provides a quantitative summary of change on the auditory task over the three sessions. It does not, by itself, establish that a change transfers to other cognitive abilities or functional outcomes. The registry record does not report a threshold for a clinically meaningful difference or explain how such a threshold was selected.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous, so it can be summarized by a mean and a measure of spread. The record reports the mean and standard deviation for each arm. The mean describes the group’s average endpoint value. The standard deviation describes how dispersed individual values are around that mean. It does not show the precision of the estimated mean; a confidence interval would serve that different purpose, but confidence intervals are not reported in the registry record.

What does a positive endpoint value mean?

The registry defines the endpoint as change in threshold from the initial plateau to the end of treatment session 3. Larger, more positive values represent greater improvement, and zero represents no improvement. Because the values are log transformed, the scale is expressed as a log ratio. Interpretation should follow the registry’s stated direction rather than treating the values as raw changes in frequency or as percentages.

Why are arm summaries not a treatment comparison?

Separate means for the D-serine arms and placebo describe the observed participants in each group. A comparative analysis would estimate the difference between groups and quantify its uncertainty, using an analysis method specified for the trial. The registry record does not post such a result, nor does it report the analysis model, a confidence interval, or a p-value. Without those details, the means cannot establish whether observed between-arm differences are statistically distinguishable from chance.

Randomization supports comparison of assigned groups in a trial, but it does not remove the need to report the statistical analysis and its uncertainty. The registry records randomized allocation, but does not describe the allocation procedure or the planned analysis. The record also does not report whether the primary analysis adjusted for baseline threshold or other variables. No adjustment should be assumed.

How should the standard deviations be read?

Standard deviations quantify participant-to-participant variability within each arm. Large variability can make group means less precise, particularly when groups are small. A standard deviation does not identify the shape of the outcome distribution, show how many participants improved, or indicate whether a treatment comparison is statistically significant. The registry record does not provide individual participant data or additional distributional summaries.

General statistical context: when data are more variable than a chosen model expects, a model that assumes less variability can understate uncertainty and produce overly narrow confidence intervals. This issue is often discussed as over-dispersion for count or event data; the posted primary endpoint is continuous, and the registry does not report a model or a dispersion assessment. It would therefore be inappropriate to claim that over-dispersion was present or that a correction was used.

What can be said about precision?

Precision is usually assessed with a confidence interval around an estimate. A confidence interval represents a range of values compatible with the data under the statistical method and assumptions used; it is not a guarantee that the true effect lies within that range. No confidence interval for a treatment comparison is reported in the registry record. The arm standard deviations alone cannot substitute for one, and no interval should be inferred from the posted summaries.

The per-arm participant counts are 12 for D-serine 80 mg/kg, 9 for placebo, 12 for D-serine 100 mg/kg, and 12 for D-serine 120 mg/g. The relatively small group sizes mean that descriptive summaries can be sensitive to individual observations. The record does not provide enough information to evaluate whether the analysis accounted for missing outcome measurements or departures from the planned allocation.

What does the design imply for analysis?

The study is listed as a randomized, triple-masked, parallel-group trial. In general, parallel-group trials compare outcomes across groups assigned to different interventions, with each participant in a group. Masking can reduce the influence of expectations on trial conduct or outcome assessment, depending on who is masked and how. The registry records triple masking but does not identify the masked parties or describe masking procedures. It also does not report an analysis plan, including whether comparisons were planned separately by dose, whether a pooled dose analysis was planned, or how multiplicity would be addressed.

The registry gives sample-size assumptions for planning illustrations: two-sided significance level 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a fraction of the observed effect. Those are planning assumptions, not results from the trial and not observed power. No numerical planning targets are reported in the registry record. The registry’s own sample-size justification and its intended relationship to the four-arm design are not reported.

There are no posted secondary outcome results and no posted analyses. Thus, the appropriate statistical reading is limited to describing the endpoint definition, arm means, standard deviations, and participant counts. Comparative estimates, uncertainty intervals, hypothesis tests, and conclusions about dose ranking are not available in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("D-serine 80 mg/kg", "Placebo", "D-serine 100 mg/kg", "D-serine 120 mg/g")
n   <- c(12, 9, 12, 12)
m   <- c(13.9, 5.3, 11, -0.05)
sp  <- c(17.5, 10.8, 16.4, 14.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  D-serine 80 mg/kg  12  13.900  17.500  2.781  25.019
CARM  Placebo  9  5.300  10.800  -3.002  13.602
CARM  D-serine 100 mg/kg  12  11.000  16.400  0.580  21.420
CARM  D-serine 120 mg/g  12  -0.050  14.100  -9.009  8.909

11. Multiplicity, Missing Data and Analysis Populations

The study lists four outcome measures, but no secondary outcome results are posted. The registry record does not report a statistical analysis plan describing which outcomes or comparisons were primary for inference, how many tests were planned, or whether any adjustment for multiple comparisons was intended. With multiple doses and a placebo group, decisions about which comparisons to test and how to control the chance of false-positive findings can matter. No multiplicity method should be inferred from the listed design alone.

Missing-data handling is not reported in the registry record. It does not state how many participants had primary endpoint measurements at the scheduled assessment, whether any outcomes were missing, how missing measurements were treated, or whether sensitivity analyses were planned. The listed arm counts provide group sizes but do not establish that every randomized participant contributed an endpoint value.

The primary outcome population is described as randomized. The record does not specify whether the analysis followed an intention-to-treat principle, a per-protocol approach, or another analysis population. It does not report exclusions after randomization or how participants who did not complete all treatment sessions were handled. These details affect interpretation because different analysis populations can answer different questions and may introduce different risks of bias.

The registry lists zero posted analyses. Therefore, the reported arm-level endpoint summaries should not be treated as a complete account of the planned inferential analysis. The analysis plan, multiplicity strategy, missing-data procedures, and definition of the analyzed population are not 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 5% reporting threshold.

The serious adverse event summaries list zero affected participants in each arm: D-serine 80 mg/kg, placebo, D-serine 100 mg/kg, and D-serine 120 mg/g. The listed numbers at risk are 12, 9, 12, and 12, respectively. The record also lists zero deaths in every arm. The other adverse event summaries likewise list zero affected participants in each arm.

These figures are counts as reported in the registry, not estimates of comparative risk. The record does not provide event-specific details because no serious adverse event terms are listed. It also does not describe the adverse-event collection period, definitions, severity grading, or whether the summaries include all randomized participants or only participants with safety follow-up. Zero reported events in these groups does not demonstrate that an event is impossible or that risks are absent; it means that no affected participants are listed in these registry summaries.

The arm sizes are small, so the safety counts have limited ability to characterize uncommon events. No further safety analysis or comparison between D-serine and placebo is reported in the registry record. These numbers should be read as the posted counts, without extending them to populations or follow-up periods not described in the record.

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

The primary outcome describes change in tone-matching threshold across three treatment sessions. The posted summaries show positive mean changes in the D-serine 80 mg/kg, D-serine 100 mg/kg, and placebo arms, and a mean close to zero and slightly negative in the arm labeled D-serine 120 mg/g. The endpoint definition states that larger, more positive values represent greater improvement. The accompanying standard deviations indicate that individual results varied within each group.

These findings are descriptive. The registry record does not report a formal comparison of any D-serine dose with placebo, a confidence interval for a treatment effect, or a p-value. It is therefore not possible from the posted summaries to determine whether the differences between group means are compatible with no difference under a specified analysis. The summaries also do not establish that one dose is better than another or identify an optimal dose.

The endpoint is specific to a tone-matching task, measured at the end of the third session. It does not, by itself, demonstrate changes in memory, attention, executive functioning, speed of processing, or day-to-day functioning. Those broader concerns appear in the registry’s rationale, but corresponding results are not posted. Nor do the endpoint summaries show whether any change persisted after the third session.

The study is recorded as completed and randomized, with 45 participants enrolled. However, the small arm sizes, lack of posted inferential results, and absence of reported information on missing data and analysis populations limit what can be concluded from the endpoint summaries. The registry record also does not report a clinically meaningful threshold for the measure, so the practical importance of the numerical group means cannot be determined from the record alone.

In short, the record documents group-level outcome summaries and safety counts for a small study of D-serine doses and placebo. It does not provide enough statistical detail to establish comparative effects, quantify their precision, or support a conclusion about clinical benefit or harm.

14. Why This Trial Matters Statistically

This trial raises several statistical issues that are important when reading small, multi-arm clinical studies. First, the endpoint is a continuous change score measured from an initial plateau to a later assessment. Its direction and scale matter: the registry defines more positive values as greater improvement, and reports the values on a log-ratio scale. Clear endpoint definitions are essential for interpreting means consistently.

Second, a multi-arm design creates more than one possible comparison. The record lists three D-serine dose labels and placebo, while describing the project as an assessment of optimal dose. Without a reported comparison strategy or multiplicity plan, the reader cannot know which dose contrasts were intended to drive inference or how the risk of false-positive findings was addressed. The posted means alone cannot resolve those questions.

Third, the arm sizes are modest, and the reported standard deviations show notable variability in the endpoint. Means can conceal participant-level variation, while small groups make estimates potentially sensitive to individual observations. Confidence intervals and a clearly specified analysis would help communicate the precision of comparative estimates; these are not reported in the registry record.

Finally, a completed trial record is not necessarily a complete account of the statistical analysis. No analyses are posted, and the record does not describe missing-data handling, analysis populations, or the planned statistical model. These omissions are important because readers need more than outcome summaries to assess the strength and limitations of a randomized comparison. The case illustrates why transparent reporting of estimates, uncertainty, analysis decisions, and outcome availability is central to statistical interpretation.

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 limitations specific to this record constrain interpretation. The primary endpoint summaries are reported by arm, without a treatment-versus-placebo estimate, confidence interval, or p-value. The registry records no posted analyses, so the inferential results and their precision cannot be assessed.

Arm sizes are small: the posted groups include 12, 9, 12, and 12 participants. The standard deviations show that endpoint values varied within groups, but participant-level data and distributional summaries are not reported. It is not possible to assess outliers, skew, or how individual observations influenced the arm means.

The registry does not report the statistical analysis plan, the analysis population beyond describing the primary outcome population as randomized, the handling of missing data, or a multiplicity strategy. It does not state whether the group summaries include all randomized participants or only those with available measurements. These gaps limit assessment of potential bias and the intended interpretation of the multiple dose comparisons.

The record’s arm label “D-serine 120 mg/g” is reproduced as recorded, but its meaning is not clarified. Arm descriptions are blank. The record also does not identify who was masked, describe the randomization procedure, or provide a clinical-importance threshold for the endpoint. Finally, the primary measure is specific to a tone-matching task at the end of three sessions; longer-term outcomes and broader functional measures are not reported in the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: D-serine Augmentation of Neuroplasticity — NCT03711500.
• Registry record last updated 2022-06-14; status last verified 2022-05.
• Results first posted 2022-06-14.
• 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

NCT03711500 is a completed randomized, triple-masked, parallel-group Phase 1 and Phase 2 study sponsored by the New York State Psychiatric Institute. It enrolled 45 participants with schizophrenia or schizoaffective disorder and listed D-serine 80 mg/kg, placebo, D-serine 100 mg/kg, and D-serine 120 mg/g arms.

The primary endpoint was log-ratio change in tone-matching threshold from the initial plateau during treatment session 1 to the end of session 3. Arm-level means, standard deviations, and participant counts are posted. No inferential analysis is posted; secondary outcome results are also not reported in the registry record. The registry lists zero serious adverse events, zero other adverse events, and zero deaths in each arm. The analysis plan, missing-data handling, analysis populations, and multiplicity strategy are not reported in the registry record.