This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Folinic Acid Intervention for Autism Spectrum Disorders (NCT01602016), a randomized phase 2 study. The primary outcome is Language Improvement.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01602016 |
| Phase | Phase 2 |
| Condition | Autism Spectrum Disorder, Autistic Disorder, Autism |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 99 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Arkansas |
| Results posted | Yes |
2. Clinical Question
Population
Children with autism spectrum disorder and language impairment were the intended Phase 2 population. The study description says screening in Phase 1 was used to identify language impairment; children determined to be pre-verbal automatically qualified, while those without language impairment were not eligible. The conditions listed include Autism Spectrum Disorder, Autistic Disorder, Autism, Asperger's Syndrome, and Pervasive Development Disorders. The number who entered Phase 2, and their detailed baseline characteristics, are not reported in the registry record.
Intervention
The randomized Phase 2 intervention was folinic acid for 12 weeks. The study description also mentions language and behavioral assessments and a blood test during this phase. Details such as dose, dosing schedule, adherence, and changes in treatment are not reported in the registry record.
Comparator
The comparison was folinic acid versus an inactive placebo, in addition to the study evaluations. The registry lists randomized allocation, quadruple masking, and a parallel design. The allocation ratio and the exact people covered by masking are not reported in the registry record.
Primary question
The intended primary question was whether language changed between baseline and 12 weeks, measured using the receptive and expressive CELF language index and the preschool language scale (PLS), as needed. The record does not report an analyzed comparison, an effect estimate, or uncertainty around an estimate. It therefore does not establish the direction or magnitude of any difference between the randomized groups.
3. Trial Design
The registry describes a Phase 2 randomized, quadruple-masked, parallel-group trial sponsored by the University of Arkansas. The planned enrollment was 99. The study began in 2012-05, and primary completion was recorded as 2015-11. Its current status is TERMINATED. The registry says the study was placed on Full Clinical Hold by the FDA and terminated by the sponsor following investigator non-compliance. It also states that the sponsor was unable to completely monitor the study or resolve outstanding queries, and that the study data could not be fully validated by the sponsor.
The study description has three phases. Phase 1 was screening for language impairment, using a screening portion of the CELF. Phase 2 was the randomized comparison of folinic acid and placebo over 12 weeks, with language and behavioral assessments and a blood test described. Phase 3 was an open-label extension: children who completed Phase 2 could be eligible to receive folinic acid for 12 weeks. That extension was not described as a randomized placebo comparison, so it should not be combined with the Phase 2 contrast when interpreting the randomized question.
The registry lists the intervention names as Folinic Acid and placebo and Folinic Acid. The planned enrollment does not establish how many participants were screened, randomized, treated, or included in any analysis. Those participant counts are not reported in the registry record. The record also does not report the allocation ratio, the randomization procedure, the implementation of masking, or whether any participants or investigators became unmasked.
Because the study was terminated and the data were not fully validated, the design description should be distinguished from evidence of completed analysis. The registry lists no analysis entries for the primary outcome. As a result, the record supports a description of the intended trial question and structure, but not an estimate of the randomized treatment contrast.
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: The study sponsor (UAMS) was unable to completely monitor the study or resolve outstanding queries. The study data cannot be fully validated by the sponsor. The study was placed on Full Clinical Hold by the FDA and terminated by the sponsor as a result of investigator non-compliance.
Overall Study
| Stage | All Participants |
|---|---|
| STARTED | 0 |
| COMPLETED | 0 |
| NOT COMPLETED | 0 |
Analysis population for the primary outcome, as defined in the registry: The study sponsor (UAMS) was unable to completely monitor the study or resolve outstanding queries. The study data cannot be fully validated by the sponsor. The study was placed on Full Clinical Hold by the FDA and terminated by the sponsor as a result of investigator non-compliance.
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: The study sponsor (UAMS) was unable to completely monitor the study or resolve outstanding queries. The study data cannot be fully validated by the sponsor. The study was placed on Full Clinical Hold by the FDA and terminated by the sponsor as a result of investigator non-compliance.
| Characteristic | Unit | All Participants |
|---|---|---|
| Participants analysed | 0 | |
| Sex: Female, Male: Female | — | |
| Sex: Female, Male: Male | — |
6. Primary Endpoint
The registry lists the primary outcome as Language Improvement, measured over (baseline and 12 weeks ).
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary outcome was language improvement, assessed at baseline and 12 weeks. The registry identifies the receptive and expressive CELF language index as measures, with the preschool language scale (PLS) used as needed. These instruments were intended to capture language performance, with separate receptive and expressive aspects represented in the planned assessment. The registry does not state a single endpoint score, a scoring rule, a threshold for meaningful change, or which measure would take precedence if both CELF and PLS data were available.
Language was selected because the study focused on autism spectrum disorder with language impairment, and the registry describes language as the primary outcome. The study summary says Phase 1 screening was intended to identify children with language impairment before Phase 2. That screening strategy aligns the intended study population with the outcome domain, but it does not itself establish that the measures were complete or that a treatment difference was observed.
For a baseline-to-follow-up outcome, an analysis could compare change over time between randomized groups or compare follow-up scores while accounting for baseline scores. Those are general approaches, not methods documented for this trial. The registry record does not report the chosen score, estimand, analysis model, handling of multiple language measures, or numerical results. No conclusion about the size, direction, or precision of language change can therefore be drawn from the endpoint description alone.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a randomized Phase 2 comparison of folinic acid with placebo, but it does not report an outcome analysis for language. It lists the primary outcome and its measurement period, yet gives no group-level results, effect estimate, confidence interval, or statistical test. The registry also lists zero analysis entries. Consequently, the posted record does not show whether the groups differed, how large any difference might have been, or how precisely it was estimated.
The absence of reported results is not evidence that the groups had the same outcome. It is also not evidence that one group improved more than the other. Without analyzed participant counts and outcome data, a reader cannot distinguish among a small difference, a larger difference, substantial uncertainty, or a result that could not be analyzed. A confidence interval, if reported, would describe the range of estimates compatible with the data and analysis under its assumptions; no such interval is reported in the registry record.
Interpretation is further constrained by the sponsor's statement that it could not completely monitor the study or resolve outstanding queries and that the data could not be fully validated. The record says that the FDA placed the study on Full Clinical Hold and that the sponsor terminated it as a result of investigator non-compliance. These registry entries make it especially important not to treat the intended protocol question as a completed, validated finding. The registry does not report which participants had usable endpoint data or whether any analysis was performed outside the registry.
The adverse-event entry lists All Participants with zero participants at risk and zero affected for both serious and other events. The death field is not reported in the registry record. With zero participants listed as at risk, those entries do not establish that no adverse events occurred; they do not provide an interpretable account of safety among treated participants. The record does not give analyzed safety denominators or event summaries by randomized group.
Overall, the available information permits description of the intended study, its endpoint, and its termination, but not an efficacy or safety estimate. No claim that folinic acid improved language, failed to improve language, or had a particular safety profile is supported by the posted results in this registry record.
9. Statistical Methods Explained
The registry identifies the trial as randomized, quadruple-masked, and parallel-group. In a randomized design, assignment is intended to make the comparison between groups less susceptible to systematic differences in participant characteristics. Masking is intended to reduce the influence of knowledge about assignment on care, assessment, or reporting. These are general purposes of the design features; the registry does not describe the randomization sequence, allocation concealment, or which roles were masked in this study. A parallel design means participants are assigned to a group and assessed within that group over the study period, rather than crossing between interventions as part of the randomized comparison.
The primary outcome was language, measured at baseline and 12 weeks using the receptive and expressive CELF language index and the PLS as needed. A statistical analysis would need to define exactly how those measurements form the primary endpoint. For example, it would need to specify whether receptive and expressive scores are separate outcomes, whether a combined score is used, how the PLS is incorporated, and how repeated measurements are compared. These details are not reported in the registry record. The registry also does not report the analysis model or whether it adjusted for baseline outcome values.
In general, an effect estimate describes the contrast between groups on a defined outcome. Its interpretation depends on the outcome scale and on whether the estimate represents a difference at follow-up, a difference in change, or another prespecified quantity. A confidence interval expresses statistical uncertainty around an estimate under the model and assumptions used. A p-value describes how compatible the observed data are with a specified null hypothesis under a statistical model; it does not measure the size or clinical importance of an effect. No effect estimate, confidence interval, or p-value for the primary outcome is reported in the registry record, so none can be interpreted for this trial.
The registry lists two secondary outcome topics: improved stereotyped behavior and improved social skills. Multiple outcome measures can create multiplicity: when several hypotheses are tested, the chance of at least one apparently notable result can increase if the analysis does not account for the number of tests. General approaches include prespecifying a hierarchy, adjusting the testing procedure, or clearly identifying analyses as exploratory. The registry record does not report a multiplicity strategy, a hierarchy among the language measures, or a statistical analysis plan. It is therefore not possible to determine how any results across measures would have been interpreted.
Missing data are another key consideration in a trial with baseline and follow-up assessments. Participants may lack a follow-up measurement, and the reasons for missingness can matter for interpretation. General analysis approaches make assumptions about why data are missing and may use different methods to address incomplete observations. The registry does not report follow-up completeness, reasons for missing outcomes, an imputation method, or sensitivity analyses. It also does not identify which randomized participants, if any, were included in a primary analysis population.
The registry's enrollment figure is 99, but this is not a count of analyzed participants. The number screened, randomized, assigned to each group, treated, completing follow-up, and analyzed is not reported in the registry record. Without those counts, it is not possible to assess participant flow or determine the extent to which the analyzed population may have differed from the randomized population.
A planning calculation based on an observed effect is not the same as a result from a trial or a measure of its observed power. The general planning assumptions stated for such illustrations are a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. These are planning conventions, not a documented design justification for this study. The registry does not report a sample-size justification, a target effect, or a power calculation used by the trial investigators. Since no primary-outcome effect is reported and no analysis is listed, there is no reported trial effect to use as an empirical basis for a planning illustration.
Over-dispersion is a general issue when observed variability exceeds what a statistical model assumes. If ignored, standard errors may be too small and statistical uncertainty understated. Whether over-dispersion was relevant to the outcome measures in this study cannot be assessed from the registry record: it does not report outcome distributions, model diagnostics, or an analysis model. Similarly, interim analyses, stopping boundaries, and any statistical monitoring plan are not reported in the registry record. The documented termination is attributed to investigator non-compliance and the clinical hold, not to a reported statistical efficacy or futility decision.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome description includes receptive and expressive CELF language measures and the PLS as needed. The registry also lists secondary topics concerning stereotyped behavior and social skills. Testing multiple measures can raise multiplicity concerns because the interpretation of a set of findings depends on how many comparisons were planned and whether any adjustment or hierarchy was specified. The registry record does not report a multiplicity adjustment, a hierarchy among primary measures, or a distinction between confirmatory and exploratory analyses.
Missing-data procedures are not reported in the registry record. There are no reported counts for participants randomized, treated, completing the 12-week assessment, or included in an analysis, and no stated method for handling incomplete outcomes. Reasons for missing assessments and sensitivity analyses are also not reported. These omissions prevent assessment of whether missingness could have affected the estimated treatment contrast or its uncertainty.
The analysis populations are not described. The record does not say whether the primary analysis was intended to include all randomized participants, only participants who received treatment, or another defined group. The enrollment figure of 99 should not be interpreted as the number included in an outcome analysis. The registry lists no analysis entries, so the planned and analyzed populations cannot be compared.
The sponsor's inability to fully monitor the study, resolve outstanding queries, or fully validate the data is relevant to the reliability of any unreported analysis. However, the record does not specify which outcome records or participant data were affected. It does not report a data reconciliation process or a validated analysis dataset. These uncertainties limit assessment of both the completeness and the integrity of the endpoint evidence.
11. What the Result Does, and Does Not, Mean
The record establishes that a randomized Phase 2 trial was intended to compare folinic acid with placebo for language outcomes in children with autism spectrum disorder and language impairment. It also describes a baseline and 12-week assessment period and identifies language measures. Those details define the clinical research question; they do not answer it.
There is no reported estimate of the difference between treatment groups, no confidence interval, and no statistical test for the primary outcome. Therefore, the registry does not indicate whether language outcomes favored either group or whether any estimated difference was precise or uncertain. An unreported result should not be read as a null result, and a terminated study should not be interpreted as proof of benefit or lack of benefit.
The registry's account of the study hold, termination, monitoring difficulties, unresolved queries, and incomplete data validation adds important context. It means that the record does not offer a fully validated analysis on which to base a quantitative interpretation. The absence of participant-flow counts and analysis-population details also prevents evaluation of how much of the intended study contributed to any endpoint assessment.
The adverse-event entries do not establish the frequency of harms among treated participants because the listed at-risk counts are zero. The missing death value is not a reported absence of deaths. No comparative safety assessment can be made from these entries.
In statistical terms, the central limitation is not that the results show a particular effect with uncertainty; it is that no analyzable treatment-effect result is reported. The registry record supports conclusions about the intended design and the reasons documented for termination, but it does not support a conclusion about the effect of folinic acid on language or about comparative safety.
12. Why This Trial Matters Statistically
This trial matters statistically because it illustrates the difference between a well-defined research question and an interpretable result. The registry describes randomization, masking, a placebo comparison, a primary language outcome, and an assessment period. Those design elements specify the intended comparison, but they cannot substitute for participant flow, outcome data, and a reported analysis.
It also highlights why endpoint definition matters when more than one instrument or subscale is named. Receptive and expressive language measures and the PLS as needed may represent related but distinct measurements. Without a stated scoring rule and analysis plan, readers cannot tell which result would have answered the primary question or how multiple outcome tests would have been handled. This is a general issue for trials with several related measures, not a claim that a particular method was used.
The record also makes data quality and validation central to interpretation. The sponsor states that it could not fully monitor the study, resolve outstanding queries, or fully validate the data. These limitations are distinct from ordinary statistical uncertainty: a confidence interval can describe sampling uncertainty under an analysis, but it does not resolve concerns about data completeness or validation. Here, no outcome analysis or estimate is reported in the first place.
Finally, the study's termination is documented as related to investigator non-compliance and a Full Clinical Hold, not a reported statistical finding. Distinguishing operational or regulatory reasons for stopping a trial from statistical evidence about an intervention prevents the termination itself from being mistaken for a treatment result. The record is therefore useful as an example of why design information, data integrity, and transparent outcome reporting all matter to clinical interpretation.
13. 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 primary limitation for evaluating this specific trial is the absence of reported primary-outcome results. The registry identifies language improvement as the endpoint but provides no group summaries, effect estimates, uncertainty measures, or tests. No analysis entries are listed. The planned comparison therefore cannot be evaluated quantitatively.
The registry reports planned enrollment of 99, but does not report how many participants entered each phase, were randomized, received study treatment, completed the 12-week assessment, or contributed to an analysis. It also does not provide baseline characteristics or outcome completeness. These gaps prevent evaluation of recruitment, attrition, and the composition of any analyzed population.
Important methodological details are not reported in the registry record, including the dose and schedule, allocation ratio, randomization implementation, exact masking roles, primary scoring rule, statistical model, missing-data methods, and multiplicity plan. The record does not report a sample-size justification, interim analyses, or stopping rules. These omissions mean that the intended design cannot be fully assessed against an analysis plan.
The registry describes the study as terminated after the sponsor could not completely monitor the study or resolve outstanding queries, and says that the data could not be fully validated. It also documents a Full Clinical Hold and investigator non-compliance. The record does not specify the extent of the data affected, so the consequences for particular measurements cannot be determined. Phase 3 was an open-label extension for eligible Phase 2 completers; no results for that extension are reported, and it would not be equivalent to the randomized placebo comparison.
The adverse-event entry has zero participants listed at risk and does not report a death value. It cannot support a meaningful comparative safety assessment. Together, the missing efficacy analyses, incomplete validation, absent participant-flow information, and sparse safety reporting make the registry record insufficient for estimating benefit or harm.
14. Related Tutorials
15. Related Statistical Calculators
16. Sources
- ClinicalTrials.gov: A Folinic Acid Intervention for Autism Spectrum Disorders — NCT01602016.
- Registry record last updated 2017-10-17; status last verified 2017-09.
- Results first posted 2016-11-07.
- 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.
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17. Record Summary
NCT01602016 is a University of Arkansas-sponsored Phase 2 study titled “A Folinic Acid Intervention for Autism Spectrum Disorders.” The registry describes a randomized, quadruple-masked, parallel-group comparison of folinic acid and placebo. Planned enrollment was 99, with a 12-week Phase 2 intervention and language assessment at baseline and 12 weeks. The primary outcome was language, measured with receptive and expressive CELF language indices and the PLS as needed.
The study also described a screening phase and an open-label folinic acid extension for eligible Phase 2 completers. The status is TERMINATED. The registry says the sponsor could not completely monitor the study or resolve outstanding queries, the data could not be fully validated, and the FDA placed the study on Full Clinical Hold before sponsor termination following investigator non-compliance.
No primary-outcome analysis or treatment-effect estimate is reported in the registry record. Participant flow, missing-data procedures, analysis populations, and an interpretable adverse-event denominator are also not reported. The record describes the intended trial but does not establish an efficacy or safety result.