PART B: Efficacy and Safety of AEVI-001 in Children and Adolescents With ADHD and Without mGluR Mutations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PART B: Efficacy and Safety of AEVI-001 in Children and Adolescents With ADHD and Without mGluR Mutations (NCT03609619), a randomized phase 2 study. The primary outcome is Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale, Version 5 (ADHD-RS-5) Total Score.

2. Clinical Question

The primary endpoint was a continuous symptom-scale measure. The registry reports least-squares mean changes for each group and a mean difference comparing AEVI-001 with placebo. A negative change on this scale represents a lower score at the later assessment than at baseline; the scale description notes that higher total scores indicate greater symptom severity.

The clinical question is specific to the Part B population and its stated genetic eligibility. The study title covers children and adolescents with and without copy number variants, but the Part B description says that this part assessed participants without the specified variants. The registry does not report a separate comparison by genetic status for these results. The posted results therefore address the study’s stated Part B population, not every population named in the broader study title.

3. Trial Design

This was Part B of a two-part, phase 2 study of AEVI-001 in children and adolescents with attention deficit hyperactivity disorder. The registry describes a multicenter, randomized, double-blind, placebo-controlled, parallel-design trial lasting six weeks. Part B focused on participants without copy number variants in the specified genes associated with glutamatergic signaling and neuronal connectivity. The study was listed as completed.

Participants were assigned to AEVI-001 or placebo. The primary endpoint was change from baseline in ADHD-RS-5 total score from baseline to Visit 8 (Week 6). The reported primary endpoint groups included 52 participants assigned to AEVI-001 and 54 assigned to placebo. The registry record lists an enrollment of 109; it does not explain the difference between that enrollment figure and the endpoint group counts.

The study also listed Clinical Global Impression - Global Improvement response from Visit 3 to Visit 8 (Week 6) as a secondary outcome. The registry contains results for that outcome, but reported analyses for it are not listed. The arm descriptions do not provide additional details about treatment schedules or dose levels.

The registry record lists a start date of 2018-08-17 and a primary completion date of 2018-11-23. It does not report the original sample-size justification, the trial’s planned statistical analysis details, or whether interim analyses were conducted. Those omissions limit how fully the planned design can be compared with the posted results.

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:

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: ITT Analysis Set

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale, Version 5 (ADHD-RS-5) Total Score, measured over Baseline to Visit 8 (Week 6).

The primary endpoint was change from baseline in the total score on the ADHD Rating Scale, Version 5 (ADHD-RS-5), between baseline and Visit 8 (Week 6). The scale description says that the total is calculated from 18 frequency items. Each frequency item is scored from 0, meaning Never or rarely, to 3, meaning Very often. The total score ranges from 0 to 54, with higher scores indicating greater symptom severity.

Change was defined as the assessment value minus the baseline value. Thus, a negative change means that the Week 6 score was lower than the baseline score. The reported group results are least-squares means, with standard errors as their accompanying measure of dispersion. Least-squares means are model-based group estimates; the particular model and its covariates are not reported in the registry record.

As a continuous endpoint, the score retains information about the degree of change rather than reducing each participant’s result to a response/nonresponse category. This can make it useful for describing average change across the group. It does not, by itself, describe the range of individual participant experiences or establish what magnitude of change would be clinically important. A threshold for clinically meaningful change is not reported in the registry record.

7. Results Posted in the Registry

• AEVI-001: mean -11.04 versus -10.38 on control; difference -0.66 (95% CI -5.35 to 4.03), standardized effect d = -0.05; z-test p = 0.783.

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.

Clinical Global Impression - Global Improvement (CGI -I) Response

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • AEVI-001: 28.8% (15/52) versus 29.6% (16/54) on control; risk difference -0.8 percentage points (95% CI -18.1 to 16.5), risk ratio 0.97 (0.54–1.76); unadjusted two-proportion z-test p = 0.929.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between AEVI-001 and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists one secondary endpoint: Clinical Global Impression - Global Improvement response from Visit 3 to Visit 8 (Week 6). Its posted comparison does not suggest a clear separation between the groups, and the interval includes no difference. This broad pattern is consistent with the primary comparison’s estimate being close to no difference, rather than supplying a clearly divergent signal across outcomes.

The endpoints measure different things. The primary endpoint is change in a continuous symptom scale, whereas the secondary endpoint is a binary response classification. Agreement in their overall lack of a clear between-group separation can be useful context, but the measures are not interchangeable and one does not validate the other. The registry does not report a combined analysis or a formal relationship between the outcomes.

Unadjusted secondary results carry less weight for confirmatory interpretation because a study may examine several outcomes, time points, or comparisons. General: when multiple hypotheses are tested, the chance of at least one apparently unusual result can increase unless an appropriate strategy is prespecified and applied. The registry record does not report a multiplicity adjustment or hierarchy for interpreting the secondary result. The secondary finding should therefore be considered exploratory or supportive rather than treated as definitive evidence on its own.

The record lists one secondary outcome and does not list reported analyses for it. Consequently, the available entry does not show whether additional analyses, subgroup examinations, or alternative definitions were planned or performed. The result can be read as a posted outcome, while the absence of a described analysis plan limits the strength of broader conclusions from it.

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

• Clinical Global Impression - Global Improvement (CGI -I) Response

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it is a numerical change score on the ADHD-RS-5. The reported group values are least-squares means, rather than values explicitly described as raw arithmetic means. A least-squares mean is generally an estimate from a statistical model that can account for specified design features or covariates. The registry record does not state the model formula, covariates, or other adjustment details, so the exact meaning of the adjustment cannot be reconstructed from the posted information.

What does the standard error describe?

The registry gives a standard error for each group’s least-squares mean. In general, a standard error describes the statistical uncertainty in an estimated mean; it is not the same as the spread of individual participant scores. A standard error is used to express how precisely a group mean has been estimated under the analysis. The reported standard errors are 1.73 for AEVI-001 and 1.651 for placebo. The registry does not report individual participant data or standard deviations for this endpoint.

How should the mean difference be read?

The posted contrast is AEVI-001 minus placebo. Its estimate of -0.66 means that the estimated change in the AEVI-001 group was lower by that amount than the estimated change in the placebo group, using the stated contrast direction. Since more negative change scores correspond to lower follow-up scores relative to baseline, the sign gives the direction of the estimate. The magnitude and its uncertainty matter together: a point estimate alone does not show how precisely the comparison is known.

What does a confidence interval add?

In general, a confidence interval is a range of values compatible with the observed data and the statistical method used, at a stated confidence level. It communicates uncertainty around an estimate more directly than a point estimate alone. The primary comparison’s 95% confidence interval includes zero, which represents no mean difference under this contrast. The interval also spans negative and positive values, indicating that the posted data do not pin down the direction of the difference with precision. A confidence interval is not a guarantee that the true value lies within its endpoints, and it does not show the probability that a particular value is true.

What does the p-value indicate?

In general, a p-value measures how unusual the data, or data more extreme, would be under a specified null hypothesis and the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. The primary comparison has an unadjusted p-value of 0.783. The registry does not report whether the analysis adjusted for other factors or whether a different testing procedure was planned. A p-value should therefore be read alongside the estimate, confidence interval, endpoint definition, and analysis details rather than as a stand-alone conclusion.

Why can over-dispersion matter?

General: for a binary outcome, simple probability models can understate uncertainty if the observed variation is greater than the model allows. This is called over-dispersion and can arise when outcomes are more alike within groups or clusters than an independence assumption permits. Greater unexplained variation can make standard errors too small if the model does not account for it. The registry record does not describe a model for the secondary binary outcome, so it is not possible to assess whether over-dispersion was relevant or how it was handled.

The secondary endpoint is a count of participants meeting a response definition, with a risk difference reported for the comparison. In general, a risk difference expresses the difference between two group proportions, with the contrast direction determined by the order of groups. The registry also reports ratio estimates for this outcome, but the definitions and analytic details behind those estimates are not described. The secondary comparison’s uncertainty should be considered together with its unadjusted p-value and its status as a secondary outcome.

Finally, statistical methods depend on the analysis population, handling of missing data, and model assumptions. The registry results do not give the missing-data method, details of the analysis population, or diagnostic checks. These omissions do not erase the posted estimates, but they constrain independent assessment of how those estimates were obtained.

11. Confidence Intervals and Precision

Precision is reflected in the range of estimates compatible with the data under the stated statistical method. For the primary comparison, the estimated mean difference was -0.66 units, with a 95% confidence interval from -5.347 to 4.027. The interval includes zero and reaches values in both directions. This means the posted estimate is not precise enough to distinguish a small difference favoring either group from no difference on the scale, based on this interval alone.

The interval should be read in the context of the ADHD-RS-5, whose total score ranges from 0 to 54. The registry does not identify a minimum clinically important difference, so the interval cannot be translated into a conclusion about clinical importance using a threshold from the record. The point estimate is only one value within a broader range of plausible comparative effects.

The secondary response comparison also has uncertainty that includes no difference. Binary outcomes can have imprecise estimates when event counts are limited, but the registry does not provide a formal precision discussion or the analysis details needed to assess the source of uncertainty. The posted confidence interval and unadjusted p-value should be considered together rather than interpreting the point estimate alone.

Confidence intervals describe statistical uncertainty under assumptions; they do not capture every source of uncertainty. In particular, they do not account for possible limitations in the analysis population, missing-data handling, measurement, or generalizability. Several of those details are not reported in the registry 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 planning illustrations give participants per arm for the continuous and binary outcomes. They do not give total event counts. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; each planning scenario uses the stated fraction of the observed effect as the effect to detect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column means the number of participants per arm in a hypothetical study that would have an 80% probability of detecting the specified effect under the listed assumptions, if that effect and the model assumptions were correct. The 90% power column describes the corresponding planning target for a 90% probability. These are planning quantities, not descriptions of the probability that the completed trial detected an effect.

The entries are based on the observed effect, with separate scenarios for 100%, 75%, and 50% of that effect. A smaller effect is harder to distinguish from random variation, so it requires more participants under the same assumptions. In these illustrations, the displayed requirements rise as the fraction of the observed effect decreases. The exceptionally large values also reflect the small observed comparison relative to its uncertainty.

These figures are not observed power. They are planning illustrations calculated from the posted effect estimate, not evidence that a particular effect is true or that the trial was designed around it. Because the original assumptions are not reported, these calculations should not be mistaken for the study’s prospective sample-size plan.

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 = -0.660; pooled standard deviation σ = 12.302.
2. n = 2 × (1.96 + 0.842)² × 12.302² / -0.660² = 5,453.5, rounded up to 5,454 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 <- -0.659999999999998                      # observed difference in means
sigma <- 12.3016623571776                     # 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(3609619)
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 = 5,454 (80% power), 7,301 (90% power)
 75% of observed effect: n per arm = 9,696 (80% power), 12,980 (90% power)
 50% of observed effect: n per arm = 21,815 (80% power), 29,203 (90% power)
power.t.test: 5454.5 
Simulated power at n = 5,454 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. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when a study evaluates more than one outcome or makes multiple statistical comparisons. In general, if each test is treated as an independent opportunity to detect a difference, the chance of at least one false-positive result can rise as the number of tests increases. Prespecified outcome hierarchies, adjusted significance thresholds, or other strategies can address this issue, but the registry record does not report a multiplicity procedure for the posted outcomes.

The record identifies a primary continuous endpoint and one secondary binary endpoint. The primary and secondary comparisons have unadjusted p-values. The secondary result should not be treated as confirmatory without knowing whether it was part of a prespecified testing sequence or subject to adjustment. The planned statistical analysis, including any hierarchy or multiplicity control, is not reported in the registry record.

Missing-data methods are also not reported. For a change-from-baseline endpoint, the handling of participants without a Week 6 measurement can affect which observations contribute to the estimate. The registry does not state whether missing values were imputed, whether a model used available measurements, or whether sensitivity analyses were conducted. The participant counts associated with posted outcome summaries do not by themselves identify the method for handling missing data.

The analysis population is not described in the registry record. It is therefore not possible to determine from the entry whether the primary results used all randomized participants, participants who received treatment, or another analysis set. The model specification, covariates, protocol deviations, and interim analyses are also not reported. These gaps limit assessment of whether the posted analysis followed a prespecified plan and how robust the findings are to alternative analytical choices.

These omissions are distinct from the reported estimates themselves. The results remain interpretable as registry-posted comparisons, but the record does not provide enough methodological detail to fully evaluate multiplicity control, missing-data assumptions, or population selection.

15. 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 non-serious adverse event terms

The registry reports no serious adverse events among the participants listed as at risk in either group. The serious-event risk denominators are 53 for AEVI-001 and 55 for placebo. Deaths are reported as zero in both groups.

For other adverse events, the registry lists 3 affected participants among 53 at risk in the AEVI-001 group and 9 among 53 at risk in the placebo group. These are descriptive counts. The record does not provide event terms, severity details, exposure-adjusted rates, or a statistical comparison for these figures, so they should not be read as evidence of a causal difference between groups.

Safety summaries depend on how events were defined, collected, and attributed. The registry entry does not provide enough detail to assess those procedures or the timing of individual events. The absence of reported serious events in these groups is a description of the posted record, not a guarantee that serious events cannot occur.

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

The results describe a randomized comparison of AEVI-001 with placebo over six weeks in Part B, which focused on children and adolescents with ADHD without the specified copy number variants. For the primary ADHD-RS-5 change outcome, the estimated mean difference was small relative to the uncertainty around it, and the confidence interval included values on either side of no difference. The posted secondary response comparison likewise does not establish a clear separation between groups.

These findings do not prove that the groups are equivalent. Establishing equivalence requires a prespecified margin and an analysis designed to test whether differences lie within that margin; neither is reported in the registry record. A non-significant p-value is not proof of no effect. The primary interval permits a range of comparative values, and the registry does not identify which magnitudes would be clinically important.

The findings also do not establish a result for participants with the specified variants, for populations outside the stated ages, or for treatment periods beyond the study’s six-week duration. The registry record does not describe enough about the statistical plan, analysis population, or missing-data handling to resolve all questions about how the estimates were generated.

The appropriate interpretation is therefore bounded: the posted data show the reported group changes and comparisons for this trial part, with uncertainty that does not support a precise conclusion about the between-group difference. They do not, on their own, settle broader questions about efficacy, safety, clinical importance, or generalizability.

17. Why This Trial Matters Statistically

This trial illustrates why a comparison should be read through both its estimate and its uncertainty. The primary point estimate is near zero, but the confidence interval is broad enough to include differences in either direction. The p-value alone would hide that range. For biostatistical interpretation, the interval and endpoint scale are essential context for understanding what the data can and cannot distinguish.

It also illustrates that two endpoint types can tell related but nonidentical stories. ADHD-RS-5 change is continuous, while the secondary response measure classifies participants into a binary outcome. Considering both can provide complementary context, but their results should not be combined informally or treated as independent confirmation without a prespecified analysis strategy.

The planning illustrations highlight a further issue: sample-size calculations that use an observed effect are not a substitute for the original design rationale. Their assumptions are explicitly illustrative, and their outputs depend on the effect selected for detection. The registry does not report the original design assumptions, so prospective intent cannot be inferred from the posted planning numbers.

Finally, registry entries can make results available while leaving important statistical details undocumented. Here, the outcome definitions and group summaries are present, but the analysis model, multiplicity strategy, missing-data method, and analysis population are not reported. Recognizing the distinction between a reported estimate and an adequately described analysis is central to evaluating clinical trial evidence responsibly.

18. 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 leaves several trial-specific limitations in assessing the posted estimates. Although the study is described as randomized and double-blind, the arm descriptions do not specify dose levels, treatment schedules, or other implementation details. The planned statistical model and its covariates are not reported, despite the primary endpoint being presented as least-squares means.

The Part B population is restricted by the absence of copy number variants in the specified genes. This limits how directly the results address the broader study population named in the title, which includes participants with and without such variants. The record does not provide separate results by genetic status or a comparison of Part B with the other study part.

The primary endpoint is assessed through Week 6, and the secondary outcome also ends at Week 6. These posted results therefore do not describe longer-term outcomes. A threshold for clinically important change is not reported, limiting interpretation of the scale difference in clinical terms.

The original sample-size rationale, multiplicity approach, missing-data methods, analysis population, and interim analysis status are not reported. The registry lists 109 enrolled, while the primary endpoint arm counts are 52 and 54; it does not explain that difference. The safety denominators also differ from the primary outcome group counts, and the entry does not explain the reasons. These reporting gaps restrict assessment of attrition, analysis choices, and the degree to which conclusions might change under alternative assumptions.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: PART B: Efficacy and Safety of AEVI-001 in Children and Adolescents With ADHD and Without mGluR Mutations — NCT03609619.
• Registry record last updated 2021-07-30; status last verified 2019-06.
• Results first posted 2019-07-16.
• 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.

22. Record Summary

The registry record describes a completed phase 2, randomized, double-blind, parallel-group, placebo-controlled study of AEVI-001 in children and adolescents with ADHD. Part B assessed participants without copy number variants in the specified genes. The primary endpoint was change in ADHD-RS-5 total score from baseline to Week 6.

The posted primary comparison was a mean difference of -0.66 units, with a 95% confidence interval from -5.347 to 4.027 and an unadjusted p-value of 0.783. The registry also reports one secondary response outcome and adverse-event summaries. The record does not report the original sample-size justification, analysis population, missing-data method, or multiplicity strategy. Interpretation is therefore limited to the posted comparisons and their stated uncertainty.