Phase IIa L-serine Trial for eAD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase IIa L-serine Trial for eAD (NCT03062449), a randomized phase 2 study. The primary outcome is Change in Score on the Montreal Cognitive Assessment Assessment Evaluation.

2. Clinical Question

3. Trial Design

This was a Phase IIa, randomized, double-blind, placebo-controlled study of L-serine in early-stage Alzheimer’s disease. The registry describes a parallel-group design and quadruple masking. Participants were assigned to an L-serine gummy arm or a placebo gummy arm. The brief summary says the investigator and study staff were blinded to group assignments; the registry’s masking classification is broader, but the record does not describe each masked role separately.

The registry records enrollment of 29. The brief summary says up to 40 subjects were to be enrolled. These are different descriptions: the former is the registered enrollment figure, while the latter is the stated recruitment ceiling in the brief summary. The record does not explain the difference or provide a recruitment history.

The L-serine arm description specifies a dose schedule after an initial ascending-dose period, while the placebo arm description specifies gummies taken two times a day. The study status is terminated. The primary outcome timeframe lists baseline, 6 Months, and 9 Months, but the registry does not report completion of those visits or the number of observations available at each time.

The primary completion date recorded in the registry is 2021-07-20. Separately, the primary-outcome description states that the investigator and institution closed the study before completion because the manufacturer’s investigational-agent stability data were judged unsatisfactory. The record cautions that the data may be invalid because of inadequate stability. It does not describe further operational details or a completed final analysis.

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: Study participants are grouped for the participant flow. The study was closed by the Sponsor-Investigator and institution prior to study completion because the stability of the investigational product could not be verified.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Investigational agent stability data provided by product's manufacturer was determined to be unsatisfactory by the Sponsor-Investigator (PI) and institutional officials. The study was closed by the PI and institution prior to study completion. Data are potentially invalid due to the inadequate stability testing performed by the manufacturer, as the sponsor-investigator is unable to confirm that the investigational product remained stable over time. No reportable study outcome data are available.

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: All study participants are grouped for the baseline measure and reported for all participants collectively. The study was closed by the PI and institution prior to study completion because the stability of the investigational product could not be verified.

6. Primary Endpoint

The registry lists the primary outcome as Change in Score on the Montreal Cognitive Assessment Assessment Evaluation, measured over Baseline, 6 Months, 9 Months.

The primary endpoint was change in score on the Montreal Cognitive Assessment, or MoCA. The registry describes the MoCA as an assessment of cognitive function across domains including visuospatial and executive function, naming, memory, attention, language, abstraction, and orientation. Its recorded score scale ranges from 0 to 30, and the record says higher values represent a better outcome. It also states that a score less than 26 is considered mild cognitive impairment.

A cognitive assessment is used in a study of early Alzheimer’s disease to quantify performance on the abilities covered by the instrument. Assessing participants at more than one visit can describe how scores change over the study period. For a randomized trial, a treatment comparison would ordinarily need to specify how change is defined and which visits or time contrast are being compared. The registry lists baseline, 6 Months, and 9 Months, but does not identify one time contrast as the reported primary analysis.

The record does not report group-level MoCA scores, change estimates, a difference between arms, confidence intervals, or a p-value. It also cautions that the data may be invalid because of inadequate investigational-agent stability. The endpoint therefore defines the intended outcome, but the registry record does not support interpreting a numerical treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a randomized, parallel-group comparison mean?

In a randomized trial, assignment to groups is determined by a random process rather than by participants or investigators choosing a treatment. Randomization is intended to reduce systematic differences between groups at the start of the comparison. It does not guarantee that groups will be identical, especially in a small study, and it does not resolve problems that occur after assignment, such as missing follow-up or concerns about the study product.

A parallel-group design assigns each participant to one study arm and compares outcomes between arms. Here, the arms were L-serine gummies and placebo gummies. Masking can reduce the influence of knowledge about assignment on participant reports, clinical care, outcome assessment, or analysis. The registry classifies this trial as quadruple-masked and the brief summary says the investigator and study staff were blinded. The record does not explain exactly which roles were included in the quadruple-masking classification.

What would an endpoint comparison require?

A treatment-effect analysis needs a defined outcome contrast. For a repeated measure such as MoCA, that could involve a comparison of scores at a specified visit, change from baseline at a specified visit, or a model using observations across visits. These approaches answer related but not identical questions. A reader needs to know which contrast was selected, how repeated measurements were handled, which participants were included, and how uncertainty was estimated.

The registry lists baseline, 6 Months, and 9 Months as the primary-outcome timeframe but does not post a single treatment comparison. It explicitly notes that the primary outcome has several categories or time points and was not reduced to one comparison. The record does not report a statistical model, a definition of change for the analysis, an estimate, or its standard error. Those details are not reported in the registry record, so no inferential result can be reconstructed from the outcome description alone.

How should estimates and confidence intervals be read?

General statistical explanation: An estimate expresses the observed size and direction of a contrast, while a confidence interval describes the statistical uncertainty around that estimate under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, but precision alone does not address bias, validity of measurement, or whether the analysis answers the clinically relevant question. A p-value, when reported, summarizes how compatible the observed data are with a specified null hypothesis under a statistical model; it does not measure the probability that a treatment works.

No treatment-effect estimate, confidence interval, or p-value for the primary endpoint is reported in the registry record. It is therefore not possible to assess precision or statistical compatibility for that outcome from the posted registry information.

What do the planning illustrations represent?

General statistical explanation: A sample-size calculation is a planning exercise. It estimates how much information a future study might need under specified assumptions, such as a target effect, significance level, allocation, and statistical model. Such a calculation does not show that an existing trial had a particular probability of detecting an effect, and it does not substitute for an observed treatment-effect estimate. Power calculated from a planned effect is not the same as “observed power” derived from the result.

The registry’s planning description says its illustrations use the observed effect, a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. It distinguishes participant counts per arm for ordinary outcomes from total event counts for time-to-event outcomes. These are planning assumptions, not the trial’s own design justification. The registry does not report the protocol’s sample-size justification or statistical plan. Because no single primary comparison is reported, the planning assumptions should not be read as a substitute for a clearly specified primary estimate.

Why can over-dispersion matter?

General statistical explanation: Over-dispersion occurs when the observed variability in data is greater than a model assumes. If a model understates variability, its uncertainty estimates can be too small and inferential results can look more certain than warranted. The appropriate treatment of variability depends on the outcome and model. The registry record does not report an analysis model or describe over-dispersion; this is a general consideration, not a claim about this trial’s data.

What does the stability caveat change?

Statistical methods rely on measurements and treatment conditions being sufficiently well characterized for the analysis to represent the intended comparison. The registry states that the manufacturer’s stability data were judged unsatisfactory and that the study was closed before completion. It warns that the data may be invalid because of inadequate stability. The record does not specify the consequences for the amount, timing, or interpretation of exposure, and no assumptions about those consequences can be made from the posted information. A statistical model cannot, on its own, resolve a product-validity concern.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome includes MoCA assessments at baseline, 6 Months, and 9 Months, while the registry’s outcome description says the primary outcome has several categories or time points and was not reduced to one comparison. When multiple outcomes, visits, or contrasts are examined, the chance of finding an apparently notable result can increase if the analysis does not account for those multiple opportunities. A statistical plan may address this by specifying a primary contrast in advance or by using an adjustment strategy. This is a general statistical concern, not a claim that a particular adjustment was or was not performed in this trial.

The registry record does not report a multiplicity plan, a hierarchy among outcome measures, or an adjustment for multiple comparisons. It also does not report an interim-analysis plan. These details are not reported in the registry record, so it is not possible to determine how the study would have controlled interpretation across visits or outcomes.

Missing data are another concern for outcomes assessed over time. If participants do not have measurements at every visit, an analysis may rely on assumptions about why observations are missing and how those missing values relate to observed outcomes. Different assumptions can produce different estimates. The record does not report visit-level completion, reasons for missing assessments, or a missing-data method.

The registry does not identify the analysis population, such as whether the planned primary analysis included everyone randomized or a narrower group. It also does not report deviations from assigned treatment or how they would be handled. No analysis population, missing-data approach, or multiplicity method should be inferred from the trial’s randomized and masked design alone.

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: gastroenteritis (15.4%), chest pain (6.2%).

The registry lists serious adverse event figures by arm. For the L-Serine Gummy Arm, the serious-adverse-event category records 16 at risk and 1 affected; for the Placebo Gummy Arm, it records 13 at risk and 2 affected. The record lists 0 deaths in each arm. These are the registry’s posted counts, not a complete description of the events’ timing, duration, severity, or relationship to study treatment.

The record also lists gastroenteritis at 15.4% and chest pain at 6.2% among the top serious terms. It does not specify in this listing which arm each term belongs to or provide additional event-level context. These percentages should not be treated as a treatment comparison without the relevant group-specific denominators and definitions.

Adverse-event counts are descriptive. They do not, by themselves, show whether an event was caused by treatment, and a small or incomplete study may provide limited information about uncommon harms. The registry’s termination and its warning that data may be invalid because of inadequate stability are important context. The record does not report a detailed safety analysis or the method used to assess causality.

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

The record establishes that a randomized, placebo-controlled Phase IIa trial was registered to study L-serine gummies in early-stage Alzheimer’s disease, with MoCA score change identified as the primary outcome. It specifies the intended arms, masking classification, outcome timeframe, and certain safety counts. These registry entries describe the study’s design and posted information; they do not provide an estimate of the primary treatment effect.

The registry does not report a single comparison of MoCA outcomes between groups, nor does it provide an effect estimate, confidence interval, or p-value. The absence of those results is not evidence that the arms were the same, and it is not evidence that one arm was better. Without a reported contrast and its uncertainty, the size, direction, and precision of any difference are unknown from the registry record.

The registry also states that the investigator and institution closed the study before completion after judging manufacturer stability data unsatisfactory. It cautions that the data may be invalid because of inadequate stability. This limits interpretation beyond the usual uncertainty of a small or incomplete trial: the record does not tell readers which data could be affected or how the concern was handled.

Likewise, the listed serious adverse event counts and terms are descriptive registry entries, not proof of causation or a complete evaluation of comparative safety. The trial status, enrollment record, and planned regimen do not establish how many participants completed treatment or contributed to each outcome analysis.

Accordingly, the posted information can be used to understand the planned research question and the limits of what was registered, but not to conclude that L-serine does or does not affect MoCA scores or to make a treatment recommendation. Statistical uncertainty and the stated product-stability concern remain central to interpretation.

13. Why This Trial Matters Statistically

This trial illustrates why a registered endpoint and a reported result are different things. The study specifies MoCA score change as its primary outcome and lists measurement visits, but the registry does not present a single comparison between the randomized arms. Without that contrast, readers cannot assess the estimated effect or its precision, regardless of how clearly the endpoint itself is described.

The record also demonstrates the importance of interpreting statistical results alongside study conduct and data validity. A study may have randomization and masking, yet still face a concern that affects whether its observations represent the intended treatment comparison. Here, the registry says the study was closed before completion because the sponsor-investigator and institutional officials judged the product manufacturer’s stability data unsatisfactory, and it warns that data may be invalid because of inadequate stability. Statistical methods cannot remove that uncertainty.

For biostatisticians and clinical researchers, the registry entry highlights several questions that a transparent report would ordinarily answer: which time point or contrast was primary, what analysis population was used, how missing repeated measurements were handled, and how multiple outcomes or visits were addressed. Those details are not reported in the registry record.

The trial is therefore informative as a case in separating design intent from evidentiary results. Enrollment and adverse-event counts are not substitutes for an outcome analysis, and a planning calculation is not an observed treatment effect. Careful interpretation requires stating both what the registry records and what it does not establish.

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.

The principal limitation for interpreting efficacy is that the registry does not report a single primary-outcome comparison. It lists MoCA assessments at baseline, 6 Months, and 9 Months, but does not provide group results, a defined treatment contrast, or an uncertainty estimate. The record itself notes that the primary outcome was not reduced to one comparison because it has multiple categories or time points.

The study was terminated, and the primary-outcome description says it was closed before completion. The registry records enrollment of 29, while the brief summary described up to 40 subjects. It does not explain the difference or report how many participants completed visits, received the intended treatment, or contributed usable outcome data.

The registry’s specific stability caveat is consequential: manufacturer stability data were judged unsatisfactory by the sponsor-investigator and institutional officials, and the record says data may be invalid because of inadequate stability. It does not describe the nature of the issue, its scope, or any corrective action. This prevents a more detailed assessment of how the concern might affect interpretation.

Other important analysis details are not reported in the registry record, including the statistical model, analysis population, missing-data approach, multiplicity strategy, protocol-based sample-size justification, and any interim analyses. Secondary outcome results are not reported either. The adverse-event listing gives selected counts and terms but lacks detailed event descriptions and causal assessments. These limitations mean the registered information is insufficient for a full evaluation of treatment effects or comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase IIa L-serine Trial for eAD — NCT03062449.
• Registry record last updated 2024-07-03; status last verified 2024-06.
• Results first posted 2024-07-03.
• 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

NCT03062449 is a Phase IIa randomized, parallel-group, placebo-controlled trial of L-serine gummies in early-stage Alzheimer’s disease. The registry classifies the study as quadruple-masked. Enrollment is recorded as 29, and the study status is terminated.

The intended primary outcome was change in MoCA score, with assessments listed at baseline, 6 Months, and 9 Months. The record does not report a single primary comparison or its effect estimate, confidence interval, or p-value. It lists secondary outcomes concerning plasma biomarker changes and the relationship between MoCA scores and plasma biomarkers, but their results are not reported in the registry record.

The registry states that the investigator and institution closed the study before completion after manufacturer stability data were judged unsatisfactory and warns that data may be invalid because of inadequate stability. Serious adverse event counts and selected serious terms are listed, but no detailed comparative safety analysis is reported. These design and outcome details should be read alongside the absence of a reported primary result and the explicit stability caveat.