Adjuvant Treatment With a Glycine Uptake Inhibitor in Participants With Negative Symptoms of Schizophrenia (P05695) (MK-8435-001): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Adjuvant Treatment With a Glycine Uptake Inhibitor in Participants With Negative Symptoms of Schizophrenia (P05695) (MK-8435-001) (NCT00725075), a randomized phase 2 study. The primary outcome is Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at Week 12.

2. Clinical Question

The registry describes a Phase 2 efficacy trial and lists schizophrenia as the condition. The core comparison is not Org 25935 instead of antipsychotic treatment: both active-treatment groups and the placebo group continued a stable second-generation antipsychotic. The question is whether adding either Org 25935 dose was associated with a different average change in negative symptoms by the endpoint assessment. The record reports group means and standard deviations, along with sponsor-reported adjusted analyses for the primary endpoint. It does not report a formal sample-size rationale or the complete eligibility criteria.

3. Trial Design

This was a randomized, double-blind, parallel-group Phase 2 trial sponsored by Merck Sharp & Dohme LLC. The registry reports enrollment of 215 and a completed status. The recorded start date is 2007-04-10, and the primary completion date is 2008-10-24. The official title describes a multi-center, double-blind, flexible-dose efficacy trial of Org 25935 versus placebo as add-on therapy for participants with persistent negative symptoms of schizophrenia. The number of sites and the method used to generate or conceal the randomization sequence are not reported in the registry record.

Participants continued a stable dose of a second-generation antipsychotic while receiving either placebo or one of two Org 25935 dose regimens. The lower regimen is listed as 8-16 mg per day, given as 4-8 mg twice daily; the higher regimen is listed as 24-32 mg per day, given as 12-16 mg twice daily. The descriptions allow upward or downward titration within the assigned range. The registry says treatment could continue for up to 87 days. Specific adherence procedures and the extent to which participants or investigators could infer treatment assignment are not reported beyond the double-blind designation.

The primary outcome was assessed at Week 12. Its stated population includes randomized participants who received study treatment and completed at least 8 weeks of treatment. The posted primary group summaries include 62 participants in the lower-dose group, 67 in the higher-dose group, and 62 in the placebo group. Those are the outcome-specific group counts, not a replacement for the registry's enrollment figure. The registry also lists secondary outcomes involving overall schizophrenia symptoms, depression symptoms, emotion perception, reasoning, memory, and information processing. Details about the original trial's planned sample size, assumptions, analysis populations beyond the primary description, and missing-data procedures 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 maintained on a stable dose of Second Generation Antipsychotic (SGA) and received add-on therapy with MK-8435 (Org 25935). 215 participants were randomized and 214 participants were treated. There was no stratification for SGA treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received either MK-8435 (Org 25935) or placebo and who completed at least 8 weeks of treatment.

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 Change From Baseline in Modified Scale for the Assessment of Negative Symptoms (SANS 1-22 Composite Score) at Week 12, measured over Baseline and Week 12.

The primary endpoint was change from baseline in the modified Scale for the Assessment of Negative Symptoms (SANS) 1-22 composite score at Week 12. SANS is described as a clinician-rated instrument for assessing negative symptoms of schizophrenia. The modified composite excludes the attention items from the 25-item scale and uses the remaining items covering affective flattening, alogia, avolition-apathy, and anhedonia-asociality. The registry reports that the measure used data from the adjusted site rater.

Each included item is rated on a scale from 0, absent, to 5, severe. The composite has a scoring range of 0 to 110, with higher scores indicating more impairment. The endpoint is expressed as a mean change from baseline rather than as a count of participants meeting a response threshold. A negative within-group change therefore represents improvement in symptoms according to the measure's scoring description. A comparison of mean changes asks whether the average change differed between an Org 25935 group and placebo.

Using a continuous measure preserves information about the magnitude of changes across participants, but a group average does not describe every participant's experience. The registry does not report a threshold for a clinically important change, a responder definition, or a basis for interpreting a particular score difference as meaningful to participants. The score and its direction can be interpreted from the record; the clinical importance of a specific between-group difference cannot be established from these summaries alone.

7. Results Posted in the Registry

• MK-8435 (Org 25935) 8-16 mg Per Day: mean -13.50 versus -11.21 on control; difference -2.29 (95% CI -6.50 to 1.92), standardized effect d = -0.19; z-test p = 0.286.
• MK-8435 (Org 25935) 24-32 mg Per Day: mean -10.91 versus -11.21 on control; difference 0.30 (95% CI -3.69 to 4.29), standardized effect d = 0.03; z-test p = 0.883.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) for Schizophrenia at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • MK-8435 (Org 25935) 8-16 mg Per Day: mean -11.84 versus -9.73 on control; difference -2.11 (95% CI -5.91 to 1.69), standardized effect d = -0.20; z-test p = 0.276.
  • MK-8435 (Org 25935) 24-32 mg Per Day: mean -10.69 versus -9.73 on control; difference -0.96 (95% CI -4.70 to 2.78), standardized effect d = -0.09; z-test p = 0.615.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MK-8435 (Org 25935) 8-16 mg Per Day and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MK-8435 (Org 25935) 24-32 mg Per Day and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • MK-8435 (Org 25935) 8-16 mg Per Day: mean -0.95 versus -0.56 on control; difference -0.39 (95% CI -1.20 to 0.42), standardized effect d = -0.17; z-test p = 0.347.
  • MK-8435 (Org 25935) 24-32 mg Per Day: mean -0.76 versus -0.56 on control; difference -0.20 (95% CI -1.00 to 0.60), standardized effect d = -0.09; z-test p = 0.625.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MK-8435 (Org 25935) 8-16 mg Per Day and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between MK-8435 (Org 25935) 24-32 mg Per Day and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Perception of Emotions Score at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • MK-8435 (Org 25935) 8-16 mg Per Day: mean 1.42 versus -0.80 on control; difference 2.22 (95% CI 0.42 to 4.02), standardized effect d = 0.43; z-test p = 0.016.
  • MK-8435 (Org 25935) 24-32 mg Per Day: mean 1.55 versus -0.80 on control; difference 2.35 (95% CI 0.55 to 4.15), standardized effect d = 0.46; z-test p = 0.011.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for MK-8435 (Org 25935) 8-16 mg Per Day than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for MK-8435 (Org 25935) 24-32 mg Per Day than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists secondary outcomes covering overall schizophrenia symptoms, depression symptoms, emotion perception, non-verbal reasoning, verbal memory, visual memory, complex information processing, and working memory. Numerical summaries are present for some of these measures, including PANSS, CDSS, and perception of emotions. Detailed numerical results for the other listed secondary outcomes are not reported in the registry record.

Across the secondary results with numerical summaries, the pattern is not uniform. The PANSS and CDSS comparisons have confidence intervals that include zero for both dose groups. The perception-of-emotions comparisons have positive recalculated mean differences, with intervals above zero for both dose groups. These descriptive secondary findings do not change the interpretation of the primary SANS endpoint: the sponsor's adjusted primary comparisons have intervals that include zero. A result on a secondary measure addresses a different outcome and does not establish a difference on the primary measure.

The secondary results should be read with less weight than a prespecified primary result, particularly because the registry lists multiple secondary outcomes and the posted secondary analyses are unadjusted recalculations. When many outcomes are examined, some estimates may appear more compelling by chance even if there is no underlying effect. General explanation: multiplicity procedures can control the chance of false-positive findings across a set of tests, but the registry record does not report whether such procedures were used for secondary outcomes. The p-values and intervals for the secondary measures should therefore be treated as exploratory unless further analysis-plan details establish otherwise.

The record lists 12 posted secondary outcomes, but it does not provide full numerical results for each one in the information available for this analysis. It would be inappropriate to infer the direction or size of unreported outcomes. The posted numerical secondary findings can add context about the range of measures assessed, but they do not replace the primary analysis or resolve the uncertainty in its estimates.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in Total Score of Positive and Negative Syndrome Scale (PANSS) for Schizophrenia at Week 12
• Change From Baseline in the Calgary Depression Scale for Schizophrenia (CDSS) at Week 12
• Change From Baseline in Perception of Emotions Score at Week 12
• Change From Baseline in Non-Verbal Reasoning Score at Week 12
• Change From Baseline in Verbal Memory Score at Week 12
• Change From Baseline in Visual Memory Score at Week 12
• Change From Baseline in Speed of Complex Information Processing Score at Week 12
• Change From Baseline in Working Memory Score at Week 12

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, so the registry reports mean change and standard deviation for each group. It also reports sponsor analyses using ANCOVA and simple unadjusted recalculations from the posted summary statistics. These methods address related but not identical questions: the mean summaries describe observed group changes, while ANCOVA estimates a treatment contrast under the model used by the sponsor. The registry does not report the full model specification or all covariates used in that analysis.

What does a mean difference represent?

A mean difference compares the average change in one group with the average change in the placebo group. For the primary measure, negative change indicates improvement from baseline. A negative between-group estimate therefore points toward a greater average reduction in the score in the active-treatment group than in placebo; a positive estimate points in the other direction. The estimate is a summary, not a description of every participant's change.

The recalculated estimates are -2.29 for the 8-16 mg per day group versus placebo and 0.3 for the 24-32 mg per day group versus placebo. They are calculated from the posted means and standard deviations without adjustment. Because the sponsor used ANCOVA, the sponsor estimates need not match these recalculations exactly. The adjusted ANCOVA estimates are -2.26 and -0.08, respectively. The registry marks no discrepancy, and the sponsor's analyses remain the reported model-based results.

What does a confidence interval add?

A confidence interval expresses uncertainty around an estimated difference. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. It is not a guarantee that the true value falls within the particular interval, and it does not directly state the probability that the treatment effect is a specific value. For the sponsor's primary analyses, both 95% intervals extend across zero. Thus, the results are compatible with no mean difference as well as with differences in either direction within the ranges shown.

How should the p-values be read?

A p-value describes how incompatible the observed data are with a specified null model, under the analysis assumptions. It is not the probability that the null hypothesis is true, the probability that the result happened by chance, or a measure of clinical importance. The sponsor reports p = 0.267 and p = 0.966 for the two primary comparisons. The recalculated unadjusted p-values are 0.286 and 0.883. These values do not meet the conventional two-sided 0.05 threshold. They should be interpreted with the estimates and intervals rather than as stand-alone evidence.

General explanation: a null value for a difference in means is zero, because zero represents no average difference between groups. A confidence interval that includes zero does not prove that there is no effect; it indicates that the analysis does not resolve the direction and size of the difference with the reported precision. Likewise, a p-value above a threshold does not show that two treatments are equivalent. Equivalence requires a prespecified margin and an analysis designed to evaluate it, neither of which is reported in the registry record.

Why can ANCOVA and an unadjusted comparison differ?

ANCOVA is a regression method that compares outcomes while accounting for specified variables in the model. In a baseline-adjusted analysis, this can account for baseline outcome values and any other included covariates. General explanation: adjustment can improve precision when variables are related to the outcome, and it can shift an estimated contrast if the modeled variables are associated with group outcomes. The registry identifies ANCOVA but does not give the complete covariate list or model details. The recalculations, by contrast, use the posted group summary statistics and are unadjusted. They are useful as a transparent check on the summaries, not as a substitute for the sponsor's model.

The standard deviations describe variability in individual scores around each group mean. The posted primary standard deviations range from 11.28 to 12.58 across the three groups. A mean difference that is small relative to the variability can be estimated imprecisely unless the study has enough information to narrow its confidence interval. General explanation: variation among participants contributes to uncertainty in comparisons, while the number of observations and the analysis design also affect precision. The registry's outcome-specific group counts are 62, 67, and 62; these counts apply to the reported endpoint summaries.

What can be inferred from the design?

Random allocation is intended, in general, to make treatment groups comparable at the start of a trial, while blinding is intended to reduce some influences of treatment knowledge on care and assessment. The registry identifies the study as randomized and double-blind, but does not report sequence generation, allocation concealment, or further masking procedures. These design labels support understanding of the trial framework but do not establish that all potential biases were prevented.

The primary endpoint population is described as randomized participants who received study treatment and completed at least 8 weeks of treatment. This is not the same as an explicit statement that all randomized participants were included in an intention-to-treat analysis. The registry does not report an intention-to-treat definition, the missing-data method, or sensitivity analyses. Such details affect how confidently the posted endpoint results can be related to the randomized comparison.

11. Confidence Intervals and Precision

The sponsor's 95% confidence interval for the 8-16 mg per day comparison runs from -6.25 to 1.74. For the 24-32 mg per day comparison, it runs from -3.91 to 3.74. Both intervals include zero, the value corresponding to no average difference. They also extend in opposite directions from zero, so the estimates do not determine whether the average change was more favorable in an Org 25935 group or in placebo.

The recalculated unadjusted intervals are -6.496 to 1.916 for the lower-dose comparison and -3.692 to 4.292 for the higher-dose comparison. These are based on posted group means and standard deviations and are not the sponsor's adjusted ANCOVA intervals. The differences between the adjusted and unadjusted estimates are small in the context of the uncertainty reflected by the intervals, and the registry marks no discrepancy. For inference about the trial's reported model, the sponsor's ANCOVA results are the relevant adjusted analyses.

Precision is about the range of values reasonably compatible with the data under the analysis, not whether an estimate is important. A wide interval leaves substantial uncertainty about the size and direction of a difference. A narrow interval can be more informative, but even a precise estimate requires a clinical context to judge its importance. No clinically important difference threshold is reported for the SANS composite, so the intervals cannot be classified against such a threshold from the registry record.

The confidence intervals also do not establish equivalence. That would require an equivalence margin and an appropriate prespecified analysis, neither of which is reported. Similarly, failure to exclude zero does not show that the groups had identical effects. The interval interpretation is limited to the endpoint population, outcome definition, and analysis actually described in the record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not a report of the trial's original design calculation. For these continuous outcomes, the figures are participants per arm, not total participants across the comparison. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial's sample-size assumptions are not reported in the registry record.

The 80% power column gives an illustrative number of participants per arm for a design that would have an 80% chance of detecting the stated effect under the listed assumptions, if that effect and the model assumptions held. The 90% power column gives the corresponding planning figure for a higher chance of detecting that effect. These are design calculations, not probabilities that the trial's result is correct, and they do not describe the power actually achieved by this trial.

Rows planning for 100%, 75%, and 50% of the observed effect illustrate how the required sample size changes with the target effect. Smaller effects are harder to detect against the same variability and therefore require more participants. This is especially important when an observed difference is small: the resulting planning figures can become very large and highly dependent on treating the observed estimate as a useful basis for a future design.

The sample-size calculations are not observed power. Observed power is not a useful substitute for reading the estimates and confidence intervals after a trial. The planning numbers are conditional illustrations and should not be taken as evidence that the original trial was designed around those assumptions or that any particular future trial should use those figures.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -2.290; pooled standard deviation σ = 11.948.
2. n = 2 × (1.96 + 0.842)² × 11.948² / -2.290² = 427.3, rounded up to 428 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -2.29                      # observed difference in means
sigma <- 11.9476943382395                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(725075)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 428 (80% power), 573 (90% power)
 75% of observed effect: n per arm = 760 (80% power), 1,017 (90% power)
 50% of observed effect: n per arm = 1,710 (80% power), 2,289 (90% power)
power.t.test: 428.3 
Simulated power at n = 428 per arm: 0.797 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports sponsor analyses for both primary comparisons using ANCOVA, with mean change from baseline as the parameter and 95% confidence intervals. The adjusted estimate was -2.26 for the 8-16 mg per day group versus placebo and -0.08 for the 24-32 mg per day group versus placebo. The corresponding p-values were 0.267 and 0.966.

The posted recalculations are simple unadjusted comparisons reconstructed from group means and standard deviations. They estimate -2.29 for the lower-dose comparison and 0.3 for the higher-dose comparison, with p-values of 0.286 and 0.883. Small differences between these figures and the sponsor's estimates are expected when the calculations use different methods: the sponsor reports ANCOVA, while the recalculations do not adjust for covariates. The registry marks no discrepancy.

The sponsor's adjusted analysis is the appropriate reference for what the registry reports as its own inferential analysis. The recalculation is a check on the posted summary statistics, not a replacement analysis. Both approaches show uncertainty around the comparisons, and both reported intervals include zero. The record does not provide the full ANCOVA specification, covariates, or further details needed to reproduce the sponsor model independently.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes, and the primary endpoint includes two comparisons against placebo. Testing several outcomes and comparisons creates a multiplicity issue: the more hypotheses considered, the greater the chance that at least one result appears statistically notable by chance if all tests are treated independently at an unadjusted threshold. General explanation: family-wise error control or other prespecified multiplicity strategies can address this issue. Whether the trial used such a strategy is not reported in the registry record.

The sponsor reports ANCOVA results for the two primary comparisons, but the record does not describe whether the primary comparisons were adjusted for multiplicity, whether one comparison was designated as the key test, or what testing sequence was planned. The recalculated p-values are explicitly unadjusted. Secondary results should be considered exploratory in the absence of reported multiplicity handling, and the emotion-perception results do not override the primary endpoint findings.

The primary endpoint population is defined as randomized participants who received either active treatment or placebo and completed at least 8 weeks of treatment. The registry does not say how many randomized participants failed to meet this criterion, why they did not complete that duration, or how missing Week 12 measurements were handled. The missing-data method, imputation approach, and sensitivity analyses are not reported in the registry record. These omissions make it difficult to assess whether the observed endpoint summaries could be affected by incomplete follow-up.

The record does not state that the primary analysis followed an intention-to-treat principle, nor does it provide a detailed protocol for analysis populations. It also does not report the randomization sequence method, allocation concealment, or full ANCOVA specification. These are reporting gaps, not proof that the procedures were absent. They limit independent evaluation of the analysis choices and their robustness.

The posted primary outcome is measured at Week 12, while the treatment description allows treatment for up to 87 days. The registry does not give further detail about visit windows, handling of measurements outside the target time, or the reason for the at-least-8-weeks completion criterion. These details matter when considering which observations contributed to the reported means and how representative they are of the randomized groups.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: schizophrenia (1.4%), dizziness (1.4%), fall (1.4%), foot fracture (1.4%), convulsion (1.4%).

The registry reports serious adverse event figures by treatment group. The number at risk was 71 in the 8-16 mg per day group, 73 in the 24-32 mg per day group, and 70 in the placebo group. The corresponding numbers reported as affected by serious adverse events were 2, 2, and 1. These figures describe the safety population shown in the registry and are separate from the primary endpoint group counts.

The record also lists serious-event terms with percentages: schizophrenia, dizziness, fall, foot fracture, convulsion, and psychotic disorder are each shown as 1.4%. The listed terms are not accompanied by treatment-group-specific breakdowns, so they should not be assigned to a particular arm from this information. The registry also reports other adverse events affecting 15 participants in the lower-dose group, 26 in the higher-dose group, and 17 in the placebo group.

Deaths are not reported in the registry record. Serious-event counts are descriptive and do not, on their own, establish that treatment caused an event or that observed differences between groups reflect a treatment effect. The record's safety figures do not supply detailed timing, duration, severity beyond the serious classification, or causal assessment for each event.

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

The primary result is an uncertain comparison of average Week 12 symptom-score changes between each Org 25935 dose group and placebo, when each was added to a stable second-generation antipsychotic. The sponsor's ANCOVA confidence intervals include zero for both dose comparisons. The data therefore do not establish a between-group difference in the primary outcome. The estimates also do not demonstrate that the groups are equivalent, because an equivalence margin and a corresponding analysis are not reported.

The negative changes within all three groups indicate lower average SANS scores at Week 12 than at baseline according to the registry's scoring description. That is a within-group observation. It cannot by itself tell whether the change resulted from Org 25935, placebo, continued antipsychotic treatment, changes over time, or other influences. The randomized comparison is the relevant basis for assessing an added-treatment difference, and its estimates remain uncertain.

These results apply to the endpoint population described in the registry: randomized participants who received study treatment and completed at least 8 weeks. They should not be generalized automatically to all people with schizophrenia, to participants who did not meet that treatment-completion condition, or to treatment circumstances not represented by this trial. The registry does not report a clinically important threshold for the SANS composite, so statistical estimates cannot be translated into a judgment about clinical importance from this record alone.

The secondary results provide context across other measures but do not settle the primary question. Some reported secondary estimates differ in direction and precision, and multiplicity handling is not reported. Safety figures are also descriptive and do not establish causation. Overall, the record supports careful description of the observed estimates and their uncertainty, rather than a broad claim about effectiveness or lack of effectiveness.

18. Why This Trial Matters Statistically

This trial illustrates why treatment-group changes from baseline and treatment-group contrasts answer different questions. Each primary group had an average decrease in SANS score, but the central statistical comparison is the difference between each active-treatment group and placebo. A visible within-group improvement does not identify the added contribution of the study drug when the comparator group also changes.

It also shows why estimates, confidence intervals, and p-values should be read together. The point estimates alone can suggest a direction, but the intervals show that the primary comparisons remain compatible with values on either side of no difference. The p-values are not measures of effect size or clinical importance. The sponsor's adjusted analyses and the unadjusted recalculations lead to the same broad reading of uncertainty while reflecting different analytical methods.

The registry's primary endpoint population and incomplete reporting of missing-data and multiplicity procedures are important statistical context. A result is interpreted not only through its numerical estimate but also through who contributed data, how the comparison was modeled, and how multiple outcomes were handled. Those aspects affect how robustly the findings can be evaluated from the record.

Finally, the planning illustrations demonstrate the sensitivity of sample-size requirements to the effect targeted. They are conditional planning calculations based on observed effects, not evidence about the trial's original design or its achieved power. Together, these features make the study useful for teaching the distinction between statistical uncertainty, clinical interpretation, and the information needed for independent appraisal.

19. 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 registry record does not provide the full eligibility criteria, site count, randomization sequence method, allocation concealment procedures, detailed masking procedures, or the complete ANCOVA specification. These omissions limit independent assessment of selection, performance, and analysis features. The multi-center description appears in the official title, but the number of participating centers is not reported in the registry record.

The primary endpoint population requires receipt of study treatment and completion of at least 8 weeks. The record does not state how many randomized participants were excluded from that population or explain how missing Week 12 outcomes were handled. Without that information, the potential effect of incomplete follow-up on the endpoint estimates cannot be assessed. An intention-to-treat analysis is not explicitly reported.

The registry does not report the trial's original sample-size justification, analysis plan, multiplicity strategy, clinically important difference threshold, or a responder definition for the SANS composite. It lists several secondary outcomes, but detailed numeric results are not available for all of them in the record. The absence of such details limits evaluation of whether the analyses and interpretations were prespecified.

The available summaries are group means and standard deviations, and the sponsor's primary inferential results are reported as ANCOVA estimates. The full model details are not available for independent reproduction. The trial record describes a treatment period of up to 87 days and the primary endpoint at Week 12, but further visit-window and adherence details are not reported. These limitations restrict conclusions to the posted outcomes and populations rather than supporting broader claims.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Adjuvant Treatment With a Glycine Uptake Inhibitor in Participants With Negative Symptoms of Schizophrenia (P05695) (MK-8435-001) — NCT00725075.
• Registry record last updated 2018-10-16; status last verified 2018-09.
• Results first posted 2016-12-13.
• 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.

23. Record Summary

The registry describes a completed, randomized, double-blind, parallel-group Phase 2 trial of Org 25935 as add-on treatment to a stable second-generation antipsychotic for participants with persistent negative symptoms of schizophrenia. The primary endpoint was Week 12 change from baseline in the modified SANS 1-22 composite score, with lower scores indicating less impairment. The specified endpoint population included treated participants who completed at least 8 weeks.

The sponsor-reported ANCOVA estimates for the 8-16 mg per day and 24-32 mg per day groups versus placebo were -2.26 and -0.08, respectively; both 95% confidence intervals included zero. The simple unadjusted recalculations showed a similar broad pattern of uncertainty. Secondary outcomes and adverse-event figures add context, but multiplicity and missing-data procedures are not reported. The registry does not establish equivalence, clinical importance, or a causal explanation for every observed change.