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 Use of Liquid Stable Levothyroxine in Trisomy 21 Pediatric Patients (NCT04747275), a randomized phase 4 study. The primary outcome is Tolerability as Assessed by the CareCAT Tool.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04747275 |
| Phase | Phase 4 |
| Condition | Hypothyroidism, Trisomy 21 |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 6 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Children's Mercy Hospital Kansas City |
| Results posted | Yes |
2. Clinical Question
Population
Children with trisomy 21 and hypothyroidism were the intended population. The registry record reports that 6 subjects were enrolled and 5 completed the study. It does not provide further detail about participant characteristics or eligibility criteria in the information available for this study.
Intervention
The intervention was liquid stable levothyroxine, identified as Tirosint-SOL. Participants assigned to start with the liquid formulation received it for 8 weeks, with dose adjustments allowed based on laboratory results and clinical response. The record describes a continued same daily dose initially, subject to those adjustments.
Comparator
The comparator was oral tablet levothyroxine. Participants assigned to start with tablets continued conventional tablet therapy for 8 weeks at their current dose before crossing over to the liquid formulation. The other sequence began with liquid therapy and then crossed over to tablets.
Primary question
The primary endpoint concerned tolerability as assessed with the Care Children's Acceptance Tool (CareCAT). The stated purpose was to understand parental perceptions of liquid stable levothyroxine. The registry record does not report analyzable primary outcome results, so it does not establish how the two formulations compared on tolerability. Adherence to study medication was listed as a secondary outcome, but no analysis of that outcome is reported either.
3. Trial Design
This was a Phase 4 randomized, open-label crossover trial sponsored by Children's Mercy Hospital Kansas City. The registry record describes two treatment sequences: liquid stable levothyroxine followed by oral tablet levothyroxine, or tablets followed by the liquid formulation. Each treatment period was described as lasting 8 weeks, and total participation was described as 16 weeks. Masking was listed as none, so participants and study personnel were not reported as blinded to the formulation being taken.
The record reports an enrollment of 6. It also states that 5 subjects completed the study. No further subjects were recruited before the study closed. The status is listed as terminated. The study start date was 2021-01-18, and the primary completion date was 2021-11-01.
In a crossover design, each participant receives both treatments in sequence. This can make within-participant comparisons useful because each participant can serve as their own comparison. However, the interpretation depends on the timing of measurements and on how the analysis handles treatment period, sequence, and any effects that might persist after a participant switches treatments. The registry record does not report a washout period or a statistical model for those features.
Dose adjustments were allowed based on laboratory results and clinical response. That feature matters when interpreting a comparison because the treatment received may not be limited to an unchanged dose throughout a period. The registry record does not describe the adjustment rules in more detail. It also does not report the planned analysis population or a detailed statistical analysis plan. These omissions prevent a full assessment of how the randomized crossover design was intended to be analyzed.
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
| Stage | Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL |
|---|---|---|
| STARTED | 2 | 4 |
| COMPLETED | 2 | 3 |
| NOT COMPLETED | 0 | 1 |
Reasons for not completing this period:
| Reason | Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL |
|---|---|---|
| Study terminated | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: 6 subjects were enrolled and 5 completed the study, however, due to concerns with data collection and integrity, the overseeing Institutional Review Board determined that results for these subjects should not be analyzed. No further subjects were recruited prior to the study closing.
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: 6 subjects were enrolled and completed the study, however, due to concerns with data collection and integrity, we elected to not use those subjects data moving forward. No further subjects were recruited prior to the study closing
| Characteristic | Unit | Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL | Total |
|---|---|---|---|---|
| Participants analysed | 2 | 4 | 6 | |
| Age, Categorical: <=18 years | Participants | 2 | 4 | 6 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 | 0 | 0 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 2 | 4 | 6 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): White | Participants | 1 | 2 | 3 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 2 | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Tolerability as Assessed by the CareCAT Tool, measured over 4 months.
| 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 tolerability assessed using the Care Children's Acceptance Tool, referred to as CareCAT. The stated purpose was to use a medication tolerability questionnaire to understand parental perceptions of liquid stable levothyroxine. The timeframe was 4 months, corresponding to the overall participation period described in the registry record.
A tolerability questionnaire can capture how medication administration is experienced by a child or caregiver, including aspects that may not be represented by laboratory measurements alone. In this study, the registry description specifically frames the measure around parental perceptions of the liquid formulation. The study rationale notes that some children may need tablets crushed and suspended for administration, and proposes that ease of administration, tolerability, and palatability could be relevant to adherence. Those points explain why a caregiver-reported measure was selected; they are not evidence that one formulation was better received.
The primary endpoint has no analyzed result in the registry record. Although 6 subjects were enrolled and 5 completed the study, the record states that concerns about data collection and integrity led the overseeing Institutional Review Board to determine that the results for these subjects should not be analyzed. Consequently, no comparison of CareCAT responses between formulations can be interpreted from the posted results. Adherence to study medication was listed as a secondary outcome, but its results are also not reported.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive fact is that the trial did not produce an analyzed primary outcome result in the registry record. Five subjects completed the study, but the record states that concerns about data collection and integrity led the overseeing Institutional Review Board to determine that their results should not be analyzed. No further subjects were recruited before the study closed. Thus, the posted information does not estimate the comparative tolerability of liquid stable levothyroxine and oral tablet levothyroxine.
This is different from a finding that the treatments had similar tolerability, or that the study found no effect. Similarity would require analyzable observations and a comparison precise enough to assess whether meaningful differences were compatible with the data. No such result is reported. The absence of a primary analysis means there is no reported effect estimate, confidence interval, or inferential test for the CareCAT outcome. The registry record does not report an analysis of adherence either.
The trial used a randomized crossover structure, with participants assigned to receive the two formulations in different orders. Such a design can support a comparison within participants, but only if the measurements and analysis preserve that structure. The information available does not describe a model accounting for treatment sequence or period, nor does it report whether possible carryover was assessed. Since the primary data were not analyzed, the design cannot compensate for the lack of a valid endpoint comparison.
Safety figures are reported separately from the primary outcome. In the sequence starting with liquid therapy, 2 participants were at risk for serious adverse events and 0 were affected; 2 were at risk for other adverse events and 0 were affected. In the sequence starting with tablets, the corresponding counts were 4 at risk and 0 affected for serious adverse events, and 4 at risk and 0 affected for other adverse events. Deaths were 0 in both sequence groups. These are descriptive counts in small groups, not a precise comparative safety analysis.
The design assumptions used for any planning illustration should not be read as observed power or as evidence that the study could answer its question. A sample-size illustration is a planning calculation under stated assumptions, not an outcome. With no analyzed primary result, there is no posted treatment effect to interpret for tolerability. The study record therefore documents the question, design, enrollment, and reason the outcome data were not analyzed, but it does not establish the direction or magnitude of a treatment difference.
9. Statistical Methods Explained
The statistical interpretation is constrained by the registry record's explicit statement that the primary outcome results were not analyzed. The following concepts explain what would ordinarily matter for a randomized crossover study; they do not describe an analysis confirmed to have been performed in this trial. The registry record does not report a full statistical analysis plan.
What does randomization contribute?
Randomization assigns participants to treatment sequences by chance. In this study, one sequence began with liquid stable levothyroxine and then changed to oral tablets, while the other began with tablets and then changed to the liquid formulation. Randomizing sequence can help balance participant characteristics between those starting orders. It does not, by itself, guarantee that a treatment comparison is unbiased if outcome data are incomplete or compromised, or if the analysis does not account for the crossover structure.
Because both formulations were given to participants in sequence, the natural unit of comparison is often the participant's outcome under each treatment, rather than treating all observations as independent. A within-participant analysis can account for stable differences between participants. General statistical practice also considers treatment period and sequence: outcomes may vary over time, and the order of treatments can matter. The registry record does not report whether a paired analysis or a model including these terms was planned or performed.
Why can period and carryover matter?
In a crossover study, the outcome measured during a treatment period may reflect more than the treatment being taken at that moment. A general concern is carryover, where effects of the earlier treatment remain after switching. A washout period may be relevant in some settings, but the registry record does not report one. It also does not state whether carryover was evaluated. These are considerations for interpreting a crossover design, not evidence that carryover occurred in this study.
The two treatment periods were each described as 8 weeks, and participants were described as taking part for 16 weeks. Dose adjustments were allowed based on laboratory results and clinical response. An analysis would need to define how outcomes and dose changes were handled over time. The registry record does not report those analysis details. It is therefore not possible to determine how a future comparison might separate formulation, period, sequence, and dose-adjustment effects from the information posted.
What would an effect estimate and confidence interval mean?
In general, an effect estimate describes the observed contrast between treatments on a defined outcome. A confidence interval describes the range of values that are compatible with the data and the analysis under its assumptions. A narrow interval indicates greater precision than a wide interval; neither an estimate nor an interval alone establishes clinical importance. This trial has no reported analyzable primary outcome estimate or confidence interval, so the precision of a tolerability comparison cannot be assessed.
A hypothesis test, if used, would address how compatible the observed data are with a specified null hypothesis under the chosen model. A p-value would not measure the size or importance of a treatment difference. The registry record does not report an analyzed primary comparison or a p-value for tolerability. It would be inappropriate to infer a null result from the absence of an analysis.
Why does over-dispersion matter in general?
Some outcomes are counts or other measures whose variability may be greater than a simple model expects. This is called over-dispersion. If it is ignored, uncertainty can be understated and inferential results can be misleading. The registry record does not report an over-dispersion assessment or identify the distributional model for the CareCAT outcome. The questionnaire's scoring details are also not reported, so it is not possible to determine from the record whether this issue would apply to its analysis.
How should sample-size illustrations be read?
The planning assumptions described for sample-size illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a fraction of the observed effect. These are planning assumptions, not a reported protocol justification or evidence of an analysis conducted in the trial. The record does not report the trial's own sample-size justification. In general, sample-size calculations estimate the number of participants needed under assumptions about an effect, variability, allocation, and statistical procedure. They are not observed power, and they cannot replace an analysis of the collected outcome data.
Any calculation based on an observed effect is especially difficult to interpret when the primary outcome was not analyzed. Planning illustrations can show how assumptions affect a hypothetical design, but they cannot establish the effect in this trial. The registry record does not report inferential results from which to judge precision or statistical evidence for the primary question.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists tolerability assessed with CareCAT as the primary outcome and adherence to taking study medication as a secondary outcome. It does not report how statistical testing across these outcomes was planned or whether any multiplicity adjustment was specified. Multiplicity refers generally to the increased chance of a misleading positive finding when multiple outcomes, comparisons, or analyses are tested. Whether and how to address it depends on the planned questions and analysis strategy; that strategy is not reported in the registry record.
The endpoint description also does not give a single numeric summary or one reported contrast. The registry record notes that the primary outcome was not reduced to one comparison because it has several categories or time points. The underlying category-level results and any rules for choosing a summary are not reported. This makes it impossible to identify a specific analyzed endpoint contrast or to assess its multiplicity.
Missing-data handling is not reported. The record states that 6 subjects were enrolled and 5 completed, but it does not describe the status or primary outcome data completeness of each participant. It also does not report how missing questionnaire responses, incomplete periods, or other unavailable measurements were handled. The reason given for not analyzing the completed subjects' results was concern about data collection and integrity, as determined by the overseeing Institutional Review Board; this is distinct from a reported statistical method for handling missing data.
The analysis population is not reported. The registry record does not say whether an intention-to-treat, per-protocol, or other population was planned for the primary analysis. These labels describe different approaches to defining who contributes to an analysis, and the choice can affect interpretation. With no reported primary analysis, no population-specific estimate is available. The record also does not describe any interim analysis or monitoring plan.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | 0 | 2 | 0.0% |
| Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL | 0 | 4 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | 0 of 2 |
| Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL | 0 of 4 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Liquid Stable Levothyroxine (l-T4) TirosintSOL First, Then Oral Tablet Levothyroxine (L-T4) | 0 of 2 |
| Oral Tablet Levothyroxine (L-T4) First, Then Liquid Stable Levothyroxine (L-T4) Tirosint-SOL | 0 of 4 |
The registry record reports adverse-event counts by randomized treatment sequence. In the group that started with liquid stable levothyroxine and then received tablets, 2 participants were at risk for serious adverse events and 0 were affected. For other adverse events, 2 were at risk and 0 were affected. Deaths were 0. In the sequence that started with tablets and then received the liquid formulation, 4 participants were at risk for serious adverse events and 0 were affected; for other adverse events, 4 were at risk and 0 were affected. Deaths were 0.
These figures describe the counts recorded for the sequence groups. They do not provide a precise estimate of comparative safety, particularly because the groups are small and the record does not report event-level detail or a treatment-period analysis. In a crossover study, participants receive both formulations over time, while these figures are presented by sequence group. They should therefore not be read as a direct comparison of the risk under each formulation.
Zero affected participants in the reported counts means that no events were recorded in those categories for those groups in the registry record. It does not prove that an event is impossible or establish the absence of risk. The registry record does not report further safety analyses or additional details about event type, timing, or severity. The primary outcome was not analyzed, and the safety counts do not resolve the unanswered tolerability comparison.
12. What the Result Does, and Does Not, Mean
The record establishes that a randomized crossover study was conducted to compare liquid stable levothyroxine with oral tablet levothyroxine in children with trisomy 21 and hypothyroidism. It describes two treatment sequences, each with 8-week periods, and lists caregiver-perceived tolerability as the primary outcome. It also records adherence as a secondary outcome. These details define the research question and the intended comparison, but they do not supply an analyzed answer to that question.
The primary outcome results were not analyzed because of concerns about data collection and integrity. The overseeing Institutional Review Board determined that results for the subjects should not be analyzed, and no further subjects were recruited before the study closed. Accordingly, the posted information cannot show whether tolerability differed between formulations, by how much it may have differed, or how precisely any difference could be estimated. The same limitation applies to the listed adherence outcome, for which no analysis is reported.
The zero adverse-event counts are descriptive and should be read in the context of the small sequence groups and the absence of a reported treatment-level safety analysis. They do not establish that either formulation has no safety risk, nor do they provide a comparative estimate of risk. The record reports no deaths in either sequence group.
The study does not establish equivalence, noninferiority, superiority, or lack of effect. Those conclusions require an analyzed comparison and an appropriate interpretation of its uncertainty. No such primary comparison is available. A planning illustration, if consulted alongside the registry record, should be treated as a hypothetical design calculation under stated assumptions, not as observed power or evidence of an effect. The most defensible conclusion is that the registry documents the study's objective and design, but the primary question remains unanswered by its posted analyzed results.
13. Why This Trial Matters Statistically
This trial matters statistically because it illustrates that a randomized design does not guarantee an interpretable treatment comparison. Randomization and a crossover structure can be useful, but they depend on valid, analyzable outcome data and an analysis that matches the design. Here, the registry record reports that the primary outcome results were not analyzed because of concerns about data collection and integrity. That makes the absence of an estimate—not a null estimate—the central statistical fact.
The study also illustrates the importance of distinguishing planned measurement from usable outcome evidence. CareCAT was selected to capture parental perceptions of medication tolerability, a question connected to administration and adherence. Yet a named instrument and a stated timeframe do not themselves provide results. The record does not report the underlying outcome values, a treatment contrast, or an uncertainty measure. The listed adherence outcome likewise has no reported analysis.
The crossover structure introduces methodological considerations that are relevant even when the data cannot be analyzed. A comparison should account for observations from the same participant and consider sequence and period. Dose adjustments were allowed, and the registry does not describe how they would be reflected in an analysis. These details show why statistical planning and clear reporting are important for interpreting a trial with repeated treatment periods.
Finally, the safety counts illustrate the limits of descriptive zero-event reports. Counts of 0 affected participants in small groups can be accurately reported, but they do not provide strong precision about uncommon events or a reliable comparison between formulations. Statistical interpretation must distinguish what was recorded from what can be concluded. In this study, the registry record supports a description of design, enrollment, outcome plans, and recorded safety counts; it does not support an estimate of the primary treatment effect.
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.
Several limitations specific to this study constrain interpretation. The most consequential is that the primary outcome results were not analyzed. The record attributes this to concerns about data collection and integrity and reports that the overseeing Institutional Review Board determined that results for the subjects should not be analyzed. Without those results, the intended comparison of caregiver-perceived tolerability cannot be estimated.
The study enrolled 6 subjects, and 5 completed. No further subjects were recruited before the study closed. This leaves little information for assessing how well the study population represents the intended population or for estimating treatment differences with precision. The registry record does not report detailed participant characteristics, the reasons for non-completion, or the completeness of the primary outcome data by participant.
The registry record does not report the full statistical analysis plan, the planned analysis population, or how missing data would be handled. It also does not describe the CareCAT scoring details, the handling of its several categories or time points, or a single prespecified contrast. Without that information—and without an analysis—it is not possible to assess endpoint construction, multiplicity, or the compatibility of the analysis with the crossover design.
Although the sequences and treatment periods are described, the record does not report a washout period or an analysis addressing period, sequence, carryover, or dose adjustment. Masking was listed as none, so subjective caregiver-perceived tolerability could be susceptible to knowledge of the formulation; the registry record does not describe steps to assess or mitigate that concern. These issues do not show that bias occurred, but they limit how a hypothetical treatment comparison would be evaluated.
Safety reporting is also limited to counts by sequence group, without event-level detail or a treatment-period comparison. Those counts should not be used as a precise comparative safety estimate. The record does not report a sample-size justification, interim-analysis plan, or further statistical methods.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Use of Liquid Stable Levothyroxine in Trisomy 21 Pediatric Patients — NCT04747275.
- Registry record last updated 2023-09-13; status last verified 2023-09.
- Results first posted 2023-04-10.
- 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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18. Record Summary
NCT04747275 is a randomized, open-label, Phase 4 crossover study sponsored by Children's Mercy Hospital Kansas City. It compared liquid stable levothyroxine (Tirosint-SOL) and oral tablet levothyroxine in children with trisomy 21 and hypothyroidism. The two sequences began with different formulations and switched after 8 weeks; participation was described as 16 weeks total.
The primary outcome was tolerability assessed using the CareCAT tool, with a timeframe of 4 months. Adherence to study medication was listed as a secondary outcome. The record reports 6 subjects enrolled and 5 completing. The study status is terminated.
The primary results were not analyzed because of concerns about data collection and integrity, as determined by the overseeing Institutional Review Board. No further subjects were recruited before closure. The record reports zero serious and other adverse events in each sequence group and zero deaths. It does not report an analyzed treatment comparison, a statistical analysis plan, or a sample-size justification.