Efficacy of To Be Marketed (TBM) Cholic Acid Capsules Used to Treat Children With Inborn Errors of Bile Acid Synthesis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of To Be Marketed (TBM) Cholic Acid Capsules Used to Treat Children With Inborn Errors of Bile Acid Synthesis (NCT01115582), a na phase 3 study. The primary outcome is Serum Transaminases.

2. Clinical Question

The study asks whether serum transaminase concentrations after 30 days of treatment with a to-be-marketed (TBM) cholic acid capsule differ from the baseline values measured while children were taking the currently used cholic acid capsules prepared at Cincinnati Children's Hospital Medical Center Pharmacy. The measures of interest are alanine transaminase (ALT) and aspartate transaminase (AST), reported as concentrations in U/L.

The clinical population is children with inborn errors of bile acid synthesis who were already taking established doses of cholic acid. The registry describes patients as receiving the same treatment across the comparison: the formulation changes from the currently used capsules at baseline to the TBM capsules during the study. It therefore frames the comparison as within-person, with each participant serving as their own reference, rather than as a comparison between independently assigned treatment groups.

The primary question is about the change in serum transaminases between baseline and after 30 days on the TBM capsule. The registry does not report the baseline or post-treatment ALT and AST means, their standard deviations, or an estimated change. It also does not report a confidence interval or a test result for this comparison. As a result, the direction, size, and precision of any observed difference cannot be described from the registry record.

This distinction matters: a within-person baseline comparison can describe measurements at two time points in the same study population, but it does not by itself establish that a formulation caused a change. The study was open label, nonrandomized, and single group; no concurrent control group is described in the registry record.

3. Trial Design

This was a phase 3, open-label, single-center, nonrandomized, single-group study. The registry reports enrollment of 16 and a completed status. The study began in 2010-04, with primary completion in 2010-08. Mirum Pharmaceuticals, Inc. is listed as the sponsor.

Participants were children with inborn errors of bile acid synthesis who were taking established doses of cholic acid capsules prepared at Cincinnati Children's Hospital Medical Center Pharmacy. At baseline, they received those currently used capsules. During the study, they received the same treatment in the TBM cholic acid capsule. The registry describes baseline measurements as the reference and values after 30 days of treatment as the TBM-formulation measurements. Participants therefore served as their own controls.

The study was not masked. Allocation is listed as not applicable, consistent with the registry's single-group design rather than assignment to separate randomized arms. The intervention is listed as cholic acid, and the arm description refers to manufactured cholic acid capsules. The registry record does not report further detail about dose changes, adherence assessment, or the exact schedule of measurements beyond baseline and after 30 days for the primary outcome.

The primary outcome population is described as all patients entered and treated. Secondary outcomes listed include adverse events, blood pressure, physical examination, and total bilirubin. The record lists six outcome measures overall, but does not report outcome analysis results. It also does not report a separate concurrent comparison group. Consequently, the design supports a before-and-after description within the enrolled group, while leaving the influence of time, clinical course, and other changes during the study unresolved.

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 was performed in patients with inborn defects of bile acid synthesis currently receiving cholic acid capsules prepared by the Cincinnati Children's Hospital Medical Center (CCHMC) under IND 45,470. The study planned to include 25 patients; but only 16 patients fulfilled eligibility criteria and were willing to travel to the CCHMC.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All patients entered and treated

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Serum Transaminases, measured over At baseline and after 30 days of treatment.

The primary endpoint is serum transaminase concentration, specifically alanine transaminase (ALT) and aspartate transaminase (AST), measured in U/L. The registry specifies that these outcomes are expressed as means with standard deviations and assessed at baseline and after 30 days of treatment. The stated population is all patients entered and treated.

ALT and AST are blood measurements used to assess liver-related biochemical status. In a study of children with inborn errors of bile acid synthesis receiving cholic acid, following these measures offers a way to describe liver-related laboratory values over the treatment interval. This is a general explanation of the measures; the registry does not state a separate rationale for selecting them as the primary endpoint.

A mean describes the average measurement in the group, while a standard deviation describes the spread of individual measurements around that average. For a before-and-after study, the important comparison would be the difference between baseline and post-treatment values, ideally with an estimate of uncertainty that accounts for measurements from the same participants. However, the registry record does not report the ALT or AST means, standard deviations, changes, confidence intervals, or statistical tests. Thus, the endpoint definition is available, but its numerical results and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a continuous primary outcome, summarized using means and standard deviations, at baseline and after 30 days. It does not report the numerical outcome summaries or a statistical analysis of the paired measurements. The concepts below explain how such data are generally interpreted; they are not a claim that a particular analysis was performed in this study.

What does a mean describe?

For a continuous measure such as serum ALT or AST, the mean is the arithmetic average across the measured participants. It gives a concise description of the group's central value at a time point. The mean alone does not describe how similar or different participants' values are from one another, which is why the registry also specifies a standard deviation.

A standard deviation describes the spread of individual observations around the mean. It is not the uncertainty of the mean itself, and it is not the same as a confidence interval. A group can have a particular average with either relatively concentrated or widely dispersed individual measurements. The registry record does not report the means or standard deviations for either primary measure, so neither central tendency nor spread can be assessed from the posted results.

Why does the repeated measurement matter?

General statistical explanation: when the same participants contribute measurements at both time points, the observations are related. A comparison that accounts for this pairing focuses on each participant's change and then summarizes those changes. Treating the two time points as independent groups would fail to reflect that relationship. The record describes participants serving as their own controls, but does not report the method used to analyze the repeated measurements. It is therefore not possible to determine whether the posted analysis, if any, used a paired approach.

Pairing can account for stable differences between participants, but it does not remove all potential sources of bias. In this design, the baseline assessment comes before the assessment after 30 days of TBM treatment. Without randomization of order or a concurrent control group, a change between measurements may also reflect factors that change with time. This general design consideration applies even when a within-person comparison is statistically appropriate.

How should uncertainty be read?

General statistical explanation: a confidence interval gives a range of values compatible with the observed data under the assumptions of the analysis. Its width conveys precision: a narrower interval indicates a more precise estimate, while a wider interval indicates greater uncertainty. A p-value, when reported, describes how compatible the data are with a specified null model; it does not measure the size or clinical importance of an effect. Neither a confidence interval nor a p-value is reported for the primary endpoint in the registry record.

For these outcomes, the estimate of interest would be the change in ALT or AST between baseline and after 30 days, together with uncertainty around that change. Separate means at each time point would not, on their own, provide all the information needed to estimate uncertainty in the within-person difference; the relationship between paired measurements matters. The registry record does not report these paired data or an estimated change.

What do the planning assumptions mean?

The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect. These are planning assumptions for hypothetical calculations, not evidence that the trial itself used a two-arm design. The trial is described as a single-group, baseline-to-follow-up study.

The record notes that time-to-event planning tables use a total number of events, while other planning calculations use participants per arm. These conventions do not turn a planning illustration into an observed trial result. The registry record does not report the numerical planning illustrations or the trial's own sample-size justification. Any planning sample size is an assumption-based illustration and must not be interpreted as observed power. Observed power is not a substitute for an estimate and confidence interval describing the actual outcome data.

The record lists zero analyses. Therefore, the primary endpoint's analysis method, handling of repeated measurements, statistical model, and inferential results are not reported in the registry record. This limits the ability to reproduce or independently assess the intended analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and identifies serum transaminases as the primary outcome, with ALT and AST named in its description. Secondary outcomes listed are adverse events, blood pressure, physical examination, and total bilirubin. The record does not describe how statistical testing across multiple outcomes or multiple measurements was handled. It does not report a multiplicity adjustment, a hierarchy of tests, or whether the secondary outcomes were intended for formal inference rather than description. No such strategy should be inferred from the outcome list.

Multiplicity is a general statistical concern when several outcomes or comparisons are tested: the chance of at least one apparently unusual result can increase as the number of tests increases. A prespecified hierarchy or adjustment can address this concern, but the registry record does not report whether one was used. Since no outcome analyses are reported, the extent to which multiplicity affects any conclusions cannot be assessed.

Missing-data methods are also not reported in the registry record. The primary outcome population is described as all patients entered and treated, but the record does not state how many had evaluable measurements at each time point, whether any values were missing, or how missing measurements were handled. It does not describe imputation, exclusion rules, or sensitivity analyses. These details matter because a before-and-after comparison requires information from both time points to estimate individual changes.

The registry does not report analysis populations beyond the stated primary population, nor does it provide an analysis set or participant flow for the primary outcome. The record lists zero analyses. Thus, it is not possible to determine which participants contributed to a particular endpoint estimate or whether the analysis population differed from the population described for the outcome.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: vomiting (6.2%), fever (6.2%).

The registry reports one participant affected by a serious adverse event among 16 at risk in the Cholic Acid group. It reports nine participants affected by other adverse events among 16 at risk. These are separate reported categories; the record does not say whether any participant appears in both. They should not be added together or interpreted as a total number of affected participants.

Vomiting and fever are listed as top serious-event terms, each with a reported value of 6.2%. The registry does not provide event-specific counts alongside these percentages in the listed information, or state whether these terms occurred in the same or different participants. It does not report a causal assessment for these events. A serious adverse event is a classification of seriousness, not a determination that the study treatment caused the event.

Deaths are not reported in the registry record. The listed safety figures do not give full detail about event onset, duration, recurrence, management, or relationship to treatment. They also do not provide a comparison with an untreated or concurrent control group. These limitations mean the figures are descriptive registry entries, not a standalone estimate of treatment-attributable risk.

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

The registry record establishes that a completed study examined a TBM cholic acid capsule in children with inborn errors of bile acid synthesis. The planned primary comparison used serum ALT and AST at baseline and after 30 days of treatment. Its design is described as open label, single center, nonrandomized, and single group, with participants serving as their own controls.

What the record does not establish is the observed primary outcome. It does not report the ALT or AST values, the amount or direction of change, or uncertainty around any estimated change. There are no reported primary-outcome confidence intervals or p-values. Without these results, the laboratory comparison cannot be characterized as showing improvement, worsening, or similarity. The completed status and the existence of an endpoint definition do not supply the missing numerical result.

General statistical interpretation: a result from a before-and-after study would describe how measurements changed over time in the studied participants. Even a clear difference would not, by itself, isolate the effect of the TBM formulation, because treatment period and time are aligned and the registry describes no concurrent control group. Open-label, nonrandomized data can be informative, but they require careful interpretation in light of these design features.

The safety record provides descriptive counts and event terms, but does not establish causality. The serious and other adverse-event categories should be read as recorded, without combining their counts or assuming that reported events were caused by treatment. The registry record also does not report deaths.

In short, the record describes the study question, population, and broad design, and includes some safety information. It does not provide the primary efficacy results or the analysis details needed to judge the magnitude, precision, or statistical significance of the serum transaminase comparison.

13. Why This Trial Matters Statistically

This study is statistically notable because it compares measurements within the same participants rather than describing separate treatment arms. That structure matches the registry's account that children began on the currently used cholic acid capsules and then received the TBM capsule, with baseline values serving as the reference. Repeated measurements can be useful when each participant's own starting value is relevant to interpreting later measurements.

The design also illustrates why a within-person comparison is not equivalent to a randomized controlled comparison. General statistical context: accounting for stable differences between participants can make a paired comparison more focused, but it cannot separate a treatment-period change from other changes that occur over time. Open-label status and the absence of a concurrent control group are therefore important when considering what a difference would mean.

The registry's reporting gap is also statistically important. It specifies the primary measure, unit, summary form, and time points, but does not report the actual ALT or AST results or their analysis. A defined endpoint alone is not enough to evaluate an effect: readers need an estimate and its uncertainty to understand both the observed pattern and how precisely it is known. The record lists zero analyses, so the inferential basis for the primary comparison is not available.

The safety record provides some event counts and terms, but they are descriptive and lack a causal comparison. Overall, the study is a useful example of how a registry can describe a clinical question and a paired design while still leaving the central statistical result unavailable. Its design and reporting should be considered separately: a completed study is not necessarily a fully interpretable results record.

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 primary limitation for interpretation is that the registry record does not report the primary endpoint results. ALT and AST are identified, along with their units, summary measure, and assessment times, but the means, standard deviations, changes, and inferential statistics are absent. The size, direction, and precision of the primary comparison therefore cannot be evaluated.

The design is open label, nonrandomized, single center, and single group. Participants serve as their own controls, but the comparison is between baseline and a later assessment after 30 days. With no concurrent control group reported, changes over time cannot be distinguished from changes associated with the formulation. Open-label status may also affect measurements or reporting in ways that a masked design could reduce, although the record does not describe whether such effects occurred.

The registry does not report the statistical method for analyzing paired measurements, missing-data handling, multiplicity strategy, or analysis populations beyond the stated primary population of all patients entered and treated. It lists zero analyses. It also does not report the trial's sample-size justification. These omissions limit reproducibility and prevent assessment of whether the analysis addressed the design and data structure appropriately.

The adverse-event entries are limited: the record lists counts for serious and other affected participants and names two top serious-event terms, but does not provide detailed timing, treatment attribution, or an untreated comparison. Deaths are not reported in the registry record. The record's enrollment and single-center setting also describe a particular study population; the registry does not provide information to assess how broadly its results would apply.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy of To Be Marketed (TBM) Cholic Acid Capsules Used to Treat Children With Inborn Errors of Bile Acid Synthesis — NCT01115582.
• Registry record last updated 2023-10-03; status last verified 2023-09.
• Results first posted 2016-12-09.
• 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

The registry describes a completed phase 3, open-label, nonrandomized, single-center, single-group study of a TBM cholic acid capsule in children with inborn errors of bile acid synthesis. Enrollment is listed as 16. Participants were measured at baseline while taking currently used cholic acid capsules and after 30 days on the TBM capsule, serving as their own controls.

The primary outcome was serum ALT and AST in U/L, summarized as means and standard deviations. The registry record does not report those outcome values or their analyses. Secondary outcomes include adverse events, blood pressure, physical examination, and total bilirubin; six outcome measures are listed overall.

The safety record lists one participant with a serious adverse event and nine with other adverse events. Vomiting and fever are listed as top serious-event terms, each at 6.2%. Deaths are not reported in the registry record. The absence of primary outcome estimates and analysis details prevents assessment of the size and precision of the main comparison.