Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment (NCT03633227), a randomized phase 4 study. The primary outcome is Maximum Observed Concentration (Cmax) of Total OCA at Week 12.

2. Clinical Question

3. Trial Design

The registry describes a Phase 4, randomized, double-blind, placebo-controlled, parallel-group study with quadruple masking. Its stated purpose was to evaluate the pharmacokinetics and safety of OCA in participants with primary biliary cholangitis and moderate to severe hepatic impairment. Enrollment is reported as 22. The study status is terminated. The start date is 2018-06-22, and the primary completion date is 2021-07-09.

The planned treatment period was 48 weeks. Participants assigned to OCA were to begin with 5 mg orally once weekly. At Week 12, a dose increase to 5 mg twice weekly could be made if there were no safety concerns. Further increases were to be considered every 6 weeks based on tolerability assessments. Placebo was designed to match the once-weekly or twice-weekly schedule. Participants completing the double-blind treatment period could continue blinded treatment until all randomized participants had completed that period and the database was locked.

The registry also described an open-label extension in which all participants would receive OCA as a possibility following review of blinded safety and pharmacokinetic data. Whether that extension began or how many participants entered it is not reported in the registry record. The reason for termination and the timing of the decision are not reported in the registry record.

Randomization is intended to create groups that can be compared without deliberate assignment based on participant characteristics. Masking is intended to reduce the influence of treatment knowledge on care, reporting, and assessment. These are general design principles; the registry record does not specify which roles were included in its quadruple-masking classification. The posted primary result is a pharmacokinetic summary for one OCA regimen, rather than a randomized comparison of OCA and placebo.

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: A total of 31 participants were screened and 22 participants were randomized.

Double Blind (DB), up to Week 48

Reasons for not completing this period:

DB Extension, Week 48 up to 3 Years

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Population: participants who received OCA and had adequate concentration-time profile to characterize OCA and its conjugates and must not have had any major protocol deviations that potentially affect exposure level. Results of PK were planned to be listed by dose regimen. Participants who received planned dose regimen and had available data were included in the analysis. No participant started OCA 5 mg twice weekly or 10 mg twice weekly at Week 12.

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 Intent-to-treat (ITT) population included all randomized participants who received any amount of investigational product (OCA or placebo).

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Concentration (Cmax) of Total OCA at Week 12, measured over Pre-dose (30 minutes before administration) and 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose at Week 12.

The primary endpoint is maximum observed concentration, or Cmax, of total OCA at Week 12, expressed in nanograms per milliliter. It reflects the highest measured concentration in the scheduled concentration-time profile. The registry lists measurements before dosing and at multiple post-dose times extending to 24 hours. Total OCA combines unconjugated OCA, glyco-OCA, and tauro-OCA as a molar sum.

Pharmacokinetic measures describe how drug concentrations change over time. Cmax is one measure of exposure and is useful for characterizing the concentration peak after dosing. It can help distinguish exposure patterns across dose regimens or populations, but it is not by itself a measure of clinical benefit or harm. That distinction is especially important in this study, whose primary aim was pharmacokinetics and safety in participants with hepatic impairment.

The posted once-weekly group result is a mean Cmax of 293.0 ng/mL, with a standard deviation of 189.0, among 5 participants. The standard deviation describes the spread of individual measurements around the group mean. The registry says that pharmacokinetic results for OCA 5 mg twice weekly or 10 mg twice weekly at Week 12 are not applicable because no participant started those regimens at that time. The registry record does not report a confidence interval for the mean or a formal comparison with placebo.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant can have a numerical Cmax measurement, and the group result is summarized using a mean and standard deviation. These summaries answer different questions. The mean describes the average observed Cmax in the analyzed group. The standard deviation describes the variability among participant measurements around that average. It is not the uncertainty interval for the mean, and it does not show whether the distribution is symmetric or whether a few observations are especially influential.

What does Cmax represent?

Pharmacokinetic sampling records concentrations at planned times around a dose. Cmax is the highest observed concentration in that profile, rather than an average concentration across all sampling times. In this trial, the scheduled profile included a pre-dose measurement and post-dose measurements through 24 hours at Week 12. Total OCA includes unconjugated OCA, glyco-OCA, and tauro-OCA. The registry describes a population with an adequate concentration-time profile and no major protocol deviations that could affect exposure as the pharmacokinetic population.

In general, a concentration-time profile can be affected by sampling completeness, timing, dosing, and participant characteristics. That is why the registry's stated pharmacokinetic population definition matters: it limits the summary to participants considered suitable for characterizing exposure. The record does not report additional details about how adequacy of a profile was assessed or how any protocol deviations were handled in the analysis.

How should a mean and standard deviation be read?

The observed mean is 293.0 ng/mL for the once-weekly group. Its standard deviation is 189.0. A larger standard deviation relative to the mean can be a sign that measurements vary substantially across individuals, but the mean and standard deviation alone do not establish the pattern of variation. They do not show the minimum, maximum, median, or whether the values contain outliers. Those details are not reported in the registry record.

A confidence interval is a general statistical tool for expressing uncertainty around an estimate. It is different from a standard deviation: the standard deviation describes dispersion among observations, while a confidence interval describes uncertainty in an estimated quantity under a specified statistical procedure. No confidence interval for the primary mean is reported in the registry record. Without one, the precision of the estimated mean is not directly summarized by an interval.

Why is a treatment contrast unavailable?

A comparative analysis would normally estimate a difference or another contrast between randomized groups and quantify its uncertainty. The posted primary results contain the once-weekly OCA summary, but no placebo Cmax summary or two-arm estimate. The registry explicitly indicates that values are missing or not estimable for a two-arm comparison of the continuous endpoint. Accordingly, there is no posted contrast, standard error, confidence interval, or p-value to interpret for the primary endpoint.

Randomization is a design feature, not a substitute for an observed comparative estimate. It helps support a fair comparison when data are available and the analysis is appropriate, but it cannot supply a missing result. The registry record does not report the planned statistical model, any adjustment variables, assumptions about the distribution of Cmax, or a formal analysis plan. It is therefore not possible to describe a model-based treatment effect from the posted results.

What do the sample-size illustrations mean?

Any sample-size illustrations associated with the posted results are planning calculations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. They are illustrations of the number of participants per arm that might be needed to detect a chosen fraction of an observed effect under those assumptions. They are not the trial's original sample-size justification and are not observed power. The registry record does not report the trial's original sample-size justification or the assumptions used to design the study.

Such calculations depend on the effect used, the variability assumption, allocation, and statistical method. When the underlying comparative effect is not estimable from the posted primary values, an illustration cannot be interpreted as evidence that the trial had enough or insufficient power for its actual objective. The registry record does not report a planned power calculation or an interim analysis plan.

Why can over-dispersion matter?

Over-dispersion is a general issue in some statistical models when observed variability exceeds what a model's assumptions expect. It matters because a model that understates variability can produce uncertainty estimates that are too narrow. This trial's primary endpoint is continuous, and the registry does not report an over-dispersion assessment or a model requiring such an adjustment. The concept is therefore a general statistical consideration, not a reported feature of the primary analysis.

Different outcome types may call for different methods. Continuous score changes, participant counts in categories, and adverse-event counts do not necessarily share one analysis model. The registry lists several score outcomes and component categories, but does not report the statistical methods used for them. The posted record therefore supports a description of the endpoint types and available summaries, not a reconstruction of an unreported analysis.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("OCA 5 mg Once Weekly")
n   <- c(5)
m   <- c(293)
sp  <- c(189)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  OCA 5 mg Once Weekly  5  293.000  189.000  58.326  527.674

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes, time points, or comparisons are examined. In general, the more statistical tests that are conducted, the greater the chance of at least one apparently unusual result arising by chance if no adjustment is made. A prespecified hierarchy, adjustment procedure, or clear distinction between primary and exploratory analyses can help readers interpret a collection of results. The statistical plan for handling multiplicity is not reported in the registry record.

The registry lists 153 outcome measures and 22 posted secondary outcomes. Secondary outcomes include changes in MELD and MELD-Na at multiple weeks and extension months, changes in Child-Pugh score, and participant counts across Child-Pugh component categories. The record does not state which outcomes were included in a multiplicity adjustment, whether any hierarchy was used, or how the many scheduled measurements were handled statistically. No multiplicity-adjusted results are reported in the registry record.

Missing-data handling is also not reported in the registry record. It does not state how incomplete concentration-time profiles, missed visits, early discontinuation, or unavailable score measurements were treated. The definition of the pharmacokinetic population identifies adequate profiles and excludes major protocol deviations that could affect exposure, but the record does not give a complete account of participant flow into that population or the handling of excluded measurements.

The registry identifies several analysis populations through outcome descriptions, but a comprehensive account of all analysis populations and their denominators is not reported in the registry record. The primary pharmacokinetic summary has 5 participants in the once-weekly group; the higher OCA schedules have no Week 12 participants. No formal analysis plan, interim analysis information, or detailed missing-data strategy is reported. These omissions limit assessment of how the posted results relate to the planned analyses.

12. 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: oesophageal varices haemorrhage (30.0%), abdominal pain (16.7%), hepatic encephalopathy (16.7%), upper gastrointestinal haemorrhage (10.0%), acute myocardial infarction (10.0%).

The registry reports serious adverse event counts by group. In the placebo group, 9 of 12 participants were affected by a serious adverse event, and 10 of 12 were affected by other adverse events. In the OCA group, 7 of 10 participants were affected by a serious adverse event, and 10 of 10 were affected by other adverse events. Deaths are reported for 2 participants in each group. These are descriptive counts, not adjusted comparisons.

The listed serious adverse event terms include oesophageal varices haemorrhage at 30.0%, abdominal pain at 16.7%, hepatic encephalopathy at 16.7%, upper gastrointestinal haemorrhage at 10.0%, acute myocardial infarction at 10.0%, and cardiac arrest at 10.0%. The registry does not provide the denominators or analysis details for each listed term in the information, so the percentages should be read as registry-reported values rather than recalculated rates. A participant may experience more than one event; the record does not clarify overlap among listed terms.

Seriousness is a classification of an adverse event, not a judgment about whether the treatment caused it. These counts alone do not establish causality or support a reliable between-group safety comparison. The record does not report a formal statistical comparison for these safety counts.

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

The posted results support a narrow descriptive statement: at Week 12, the mean total OCA Cmax in the 5-person once-weekly group was 293.0 ng/mL, with a standard deviation of 189.0. This is a summary of measured drug exposure in that group. It is not an estimate of the difference between OCA and placebo, and it does not by itself describe a clinical outcome.

The result does not establish how Cmax compares across dose regimens. No participants started the 5 mg twice-weekly or 10 mg twice-weekly regimen at Week 12, and no estimates for those schedules are applicable. The posted primary result also does not include a placebo pharmacokinetic summary. A comparative effect and its precision are therefore not reported in the registry record.

The result also does not show whether OCA improves or worsens a health outcome. Although the trial included safety outcomes and registered clinical score measures, the primary endpoint is pharmacokinetic. A concentration measure can characterize exposure, but it is not interchangeable with a clinical benefit, a clinical harm, or a complete safety assessment.

The adverse-event counts provide descriptive information about participants recorded with events and deaths in each group. They do not establish that treatment caused an event, and the counts do not account for possible differences in exposure time or participant characteristics. The registry does not report a formal comparative safety analysis in the information described.

Finally, termination does not reveal why the study stopped or what conclusions the sponsor reached. The reason for termination, the extent of completed follow-up, and the status of the proposed open-label extension are not reported in the registry record. The posted data should therefore be interpreted as limited summaries rather than as a complete assessment of the study's planned questions.

14. Why This Trial Matters Statistically

This trial raises a statistical question that is distinct from a conventional efficacy comparison. Its stated focus is pharmacokinetics and safety in participants with primary biliary cholangitis and moderate to severe hepatic impairment. In that setting, a concentration-time profile and Cmax can characterize exposure in a population for whom the study was designed to examine pharmacokinetic behavior. The endpoint is therefore important for describing exposure, even though it does not directly measure a clinical outcome.

The record also illustrates how an intended dose-escalation design can differ from the data ultimately available for a particular endpoint. The protocol description included possible increases after the initial regimen, but no participants started the higher twice-weekly regimens at Week 12. Those dose groups consequently cannot contribute a Week 12 estimate for the primary outcome. The distinction between planned regimens and estimable results is essential when reading registry records.

Statistically, the key issue is the limited scope of the posted evidence. The available Cmax result is a mean and standard deviation for one regimen, without a placebo estimate or comparative uncertainty measure. This makes descriptive interpretation possible but does not support a treatment contrast. Safety counts offer another kind of summary, but they likewise should not be mistaken for a causal comparison.

The trial also registered many secondary measures across repeated time points. Multiple outcomes can offer a broad description of disease-related scores and safety, but their interpretation depends on a transparent analysis plan and clear handling of multiplicity and missing data. Those details are not reported in the registry record. The study is thus a useful example of why readers should distinguish registered outcomes, observed summaries, and formal comparative analyses.

15. 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 pharmacokinetic result is based on 5 participants in the once-weekly OCA regimen. The registry does not provide an uncertainty interval, individual observations, or a placebo Cmax summary. The small reported group and absence of a comparator estimate limit assessment of precision and prevent a direct comparative interpretation.

Higher OCA schedules have no applicable Week 12 result because no participant started those regimens at that time. This prevents interpretation of the primary endpoint across the planned dose schedules. The registry also describes a potential open-label extension, but whether it took place and what data it generated are not reported in the registry record.

The study is listed as terminated, but the reason for termination and its effect on enrollment, follow-up, or planned analyses are not reported in the registry record. Although enrollment is reported as 22, the record does not provide a complete participant-flow account in the registry record described. The timing and completeness of the safety observation period are not reported in the registry record.

Statistical methods for the primary endpoint and secondary outcomes are not reported in the registry record. This includes any model specifications, adjustment variables, multiplicity procedures, missing-data methods, interim analyses, and original sample-size justification. The registry lists numerous outcomes and time points, but the availability and analysis of all these measures cannot be inferred from their registration.

Safety summaries are counts and registry-listed event percentages, without a reported formal comparison or full event-level detail. They do not show causality, duration, or overlap between events. Together, these limitations mean the posted record supports selected descriptive observations, not a complete reconstruction of the trial's conduct or statistical analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Obeticholic Acid (OCA) Evaluating Pharmacokinetics and Safety in Participants With Primary Biliary Cholangitis (PBC) and Hepatic Impairment — NCT03633227.
• Registry record last updated 2022-09-06; status last verified 2022-08.
• Results first posted 2022-09-06.
• 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.

19. Record Summary

NCT03633227 is a terminated Phase 4 randomized, double-blind, placebo-controlled, parallel-group study sponsored by Intercept Pharmaceuticals. It was designed to evaluate OCA pharmacokinetics and safety in participants with primary biliary cholangitis and moderate to severe hepatic impairment. The registry reports enrollment of 22, a start date of 2018-06-22, and a primary completion date of 2021-07-09.

The primary endpoint is Week 12 total OCA Cmax. The once-weekly OCA group has a reported mean of 293.0 ng/mL and standard deviation of 189.0 among 5 participants. No Week 12 pharmacokinetic results apply to the higher listed OCA regimens, and a two-arm comparison is not estimable from the posted continuous endpoint values. Safety counts are reported for placebo and OCA, but a formal comparative safety analysis is not reported in the registry record. The reason for termination and detailed statistical plan are not reported in the registry record.