Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury (NCT01548690), a na phase 2 study. The primary outcome is Number of Participants That do Not Tolerate the Administered Dose and Had Grade 3 or 4 Treatment Emergent Adverse Events as a Measure of Safety and Tolerability.

2. Clinical Question

This is an early-phase safety and tolerability study, not a randomized test of comparative efficacy. Its stated hypotheses included safety and tolerability, drug concentration behavior, possible changes in ammonia, and neurological function. Those hypotheses describe questions the study was designed to address; they are not findings. The distinction matters because a study objective does not show that an outcome occurred or that a change was caused by treatment.

3. Trial Design

The registry identifies this as a Phase 2a study of ornithine phenylacetate in acute liver failure or severe acute liver injury. It is marked completed, with 47 participants enrolled. The record gives a start date of 2012-06 and a primary completion date of 2017-02-23. The sponsor is listed as William Lee. These record details describe the trial’s status and conduct but do not establish what the results mean.

The design is listed as single-group, with allocation not applicable and no masking. There is therefore no randomized control group in the record. The listed maximum-dose levels are 3.33 g/24h, 6.65 g/24h, 10 g/24h, and 20g/24h. These dose-level groupings should not be interpreted as randomized treatment arms or as equivalent to a controlled dose comparison. Differences between them could reflect how participants entered or proceeded through the study, among other possibilities not described in the record.

The intervention was administered intravenously through a peripheral venous catheter. The study summary describes infusion for up to 120 hours, followed by a 30 day follow-up visit. The primary endpoint timeframe is also given as 30 Days. The record’s brief summary says infusion rates differed and mentions patients with and without impaired renal function as part of the study aims. Further details about dose assignment, treatment interruptions, actual exposure duration, and renal-function subgroups are not reported in the registry record.

Alongside the primary safety measure, the listed secondary outcomes include plasma concentration, change in ammonia, and neurological function measured by the West Haven Criteria and the Orientation Log. There are five outcome measures in the record, but it lists zero analyses. Detailed analysis methods, endpoint results, and the handling of participants who did not complete follow-up are not reported in the registry record. Consequently, the design and objectives can be described, but the posted information does not support conclusions about the size or precision of treatment-related changes.

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

Analysis population for the primary outcome, as defined in the registry: All patients who consented to the study, completed screening and had the intravenous infusion of study drug initiated

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 Number of Participants That do Not Tolerate the Administered Dose and Had Grade 3 or 4 Treatment Emergent Adverse Events as a Measure of Safety and Tolerability, measured over 30 Days.

The primary endpoint is a count of participants meeting a combined safety definition: they did not tolerate the administered dose and had grade 3 or 4 treatment-emergent adverse events. The stated timeframe is 30 Days. The population description specifies people who consented, completed screening, and had the intravenous infusion initiated. The endpoint is therefore intended to capture participants meeting both parts of the definition, rather than all adverse events or all participants who experienced any symptom.

Safety and tolerability are central questions for an early-phase study in a serious acute illness. A count can communicate how many participants met a prespecified safety criterion, while the event definitions determine which experiences qualify. In this case, the record does not explain how dose intolerance was operationalized, how adverse-event grade was assigned, or whether the two conditions were adjudicated together. Those details are not reported in the registry record.

The endpoint result itself is not reported in the registry record. The available adverse-event listings give serious and other event counts by maximum dose level, but those listings are not the same as the primary endpoint: they do not state how many participants both failed to tolerate the dose and experienced a grade 3 or 4 treatment-emergent event. Without that result and its analysis population, the primary safety question remains unresolved in the posted results. A participant count alone would also not identify whether an event was caused by treatment; interpretation would require clinical context and the trial’s event-assessment methods.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design tell us?

In general, a single-group study describes outcomes among people receiving the study intervention without a randomized control group. It can document events observed during treatment and follow-up, and can contribute safety information. But an observed event count alone cannot separate events caused by treatment from events due to the underlying illness, other care, or chance. A control group helps estimate what would have happened under a different treatment strategy; this record does not describe one.

Here, the record identifies a single-group design, no masking, and allocation as not applicable. The dose-level entries are descriptive groupings by maximum dose level, not randomized comparator arms. In general, nonrandomized groups may differ in their baseline health, illness severity, treatment course, or other factors. Without information about those characteristics and how dose levels were reached, comparisons across the listed groups are not causal comparisons.

How should a count endpoint be understood?

In general, a count endpoint reports how many participants satisfy a defined event criterion. The definition determines what the count means. The primary endpoint in this study combines dose intolerance with grade 3 or 4 treatment-emergent adverse events, and specifies a 30 Days timeframe. It is not equivalent to the count of all participants with any adverse event, nor necessarily to the count with any serious adverse event. The registry record does not report the primary count or further operational details about dose intolerance.

A count is most interpretable alongside the number of participants assessed and the rules for inclusion in the analysis. The endpoint population is described as participants who consented, completed screening, and began infusion. The registry does not report a primary endpoint analysis population count or explain how missing follow-up data were handled. The enrolled total of 47 should not automatically be assumed to be the denominator for every outcome.

What can the adverse-event entries establish?

In general, adverse-event counts describe recorded occurrences under specified definitions and observation periods. Serious events are a subset defined by seriousness criteria; severity grade and seriousness are distinct concepts. A severe event is not automatically a serious event, and the primary endpoint’s grade 3 or 4 criterion cannot be inferred from the serious-event counts. The registry record separately gives serious and other event entries by maximum dose level, but it does not define the “other” category in the information.

Counts are descriptive. They can show how many participants in a listed group had recorded events, but they do not by themselves establish event rates over person-time, comparative risks, or treatment causation. The record does not state exposure duration for each participant, event onset times, event recurrence, or the relationship of events to study drug. Death counts also require context, including cause and timing, which are not reported in the registry record.

What is uncertainty, and why does it matter?

In general, a confidence interval expresses the range of values compatible with a statistical estimate under a specified model and sampling assumptions. It communicates precision as well as the estimate’s direction or magnitude. A count without an interval can be informative descriptively, but it does not show how uncertain an estimate of an underlying event frequency may be. The posted primary endpoint has no reported estimate or confidence interval, and no analysis is listed.

For this study, no confidence intervals, hypothesis tests, or modeled treatment contrasts are reported in the registry record. It is therefore not possible to characterize statistical precision for the primary endpoint or secondary outcomes from the listed information. General methods could be used to estimate uncertainty from suitable participant-level data, but reconstructing such an analysis would require data and assumptions not reported.

Why are dose-group comparisons especially limited?

In general, a comparison of outcome counts across dose groups can be distorted when the groups were not formed by random assignment. Participants’ health and clinical course can influence which dose they receive or reach. The record does not report the dose-escalation or dose-selection rules, so it is not possible to determine whether the listed groups are comparable. The dose labels should therefore be read as categories in the adverse-event record, not as a controlled dose-response experiment.

In general, dose-response analysis also needs a clear definition of exposure, adequate information on treatment duration, and a prespecified statistical approach. The study summary mentions different infusion rates and several maximum-dose levels, but the analysis plan and actual participant-level exposure are not reported in the registry record. A pattern across the listed event counts should not be treated as evidence of a dose effect.

What do the other outcomes contribute?

The listed secondary outcomes cover plasma concentration, ammonia, and neurological function assessed using the West Haven Criteria and the Orientation Log. In general, these measures may address pharmacokinetics, biochemical response, or clinical status, but their interpretation depends on when measurements were taken, how baseline values were defined, and how missing observations were handled. Those analysis details and the outcome results are not reported in the registry record.

The trial description includes hypotheses about achieving steady-state plasma concentrations and reducing ammonia or improving neurological function. Such statements are aims, not statistical findings. The record’s listing of an outcome does not establish that a planned analysis was conducted or that a result favored the intervention. With zero analyses listed, the registry record offers no reported statistical test or treatment-effect estimate for these secondary outcomes.

Overall, statistical interpretation should distinguish design information, observed descriptive counts, and analyzed effects. The record describes a safety-focused, single-group study and gives some adverse-event data. It does not provide the primary endpoint result, inferential analysis, or sufficient detail to evaluate comparative effects. General statistical concepts can clarify why those omissions matter, but they cannot replace missing trial results.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Maximum Dose Level 3.33 g/24h", "Maximum Dose Level 6.65 g/24h", "Maximum Dose Level 10 g/24h", "Maximum Dose Level 20g/24h")
n      <- c(9, 10, 13, 15)
events <- c(0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Maximum Dose Level 3.33 g/24h  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Maximum Dose Level 6.65 g/24h  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5
ARM  Maximum Dose Level 10 g/24h  13  0  0.0  0.0  24.7  0.0  22.8  0.2  23.2
ARM  Maximum Dose Level 20g/24h  15  0  0.0  0.0  21.8  0.0  20.4  0.2  20.6

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, subgroups, or statistical tests. In general, testing many questions can increase the chance of finding an apparently notable result by chance unless the analysis plan accounts for the number and priority of tests. The record lists a primary safety endpoint and secondary outcomes involving plasma concentration, ammonia, and two neurological measures. It does not report a multiplicity strategy, a hierarchy among secondary outcomes, or whether any adjustment for multiple testing was planned. These details are not reported in the registry record.

Missing data can affect both descriptive counts and comparisons. In general, interpretation depends on why measurements are missing and how the analysis handles participants who withdraw, die, miss visits, or lack a measurement. The primary endpoint population is described as those who consented, completed screening, and initiated infusion, but the record does not report how many contributed an endpoint assessment or how missing endpoint information was treated. It also does not report missingness details for the secondary outcomes.

Analysis populations matter because results can differ depending on whether they include everyone who began treatment, only those with complete measurements, or another defined group. The registry lists 47 enrolled participants, but does not report a primary endpoint denominator or a detailed analysis population for each outcome. The listed number of analyses is zero, and statistical methods for the posted outcomes are not reported. Accordingly, neither multiplicity control nor the effects of missing data can be evaluated from this record. These absences limit interpretation; they do not establish that a particular method was or was not used outside the registry record.

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: pneumonia (22.2%), acute hepatic failure (15.4%), hypotension (13.3%), deep vein thrombosis (11.1%), circulatory collapse (11.1%).

The serious adverse-event record gives counts within four maximum-dose groups. At 3.33 g/24h, 5 of 9 are listed as having serious adverse events and 8 of 9 as having other adverse events, with 2 deaths. At 6.65 g/24h, those entries are 3 of 10, 5 of 10, and 3 deaths. At 10 g/24h, they are 4 of 13, 9 of 13, and 2 deaths. At 20g/24h, they are 4 of 15, 7 of 15, and 4 deaths. These entries describe recorded events by the group labels in the registry.

The serious-event terms include pneumonia (22.2%), acute hepatic failure (15.4%), hypotension (13.3%), deep vein thrombosis (11.1%), circulatory collapse (11.1%), and compartment syndrome (11.1%). The record does not specify the denominator used for these percentages or whether participants could be counted under more than one term. The percentages should therefore be read as registry-listed term frequencies, not as mutually exclusive shares or as individual treatment risks.

These counts do not establish that treatment caused an event or death. The study has no randomized control group, and event attribution, timing, and causes of death are not reported in the registry record. Nor are these entries interchangeable with the primary endpoint, which requires both dose intolerance and a grade 3 or 4 treatment-emergent adverse event. That primary result is not reported in the registry record.

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

The record shows that ornithine phenylacetate was studied in a completed Phase 2a, single-group trial enrolling 47 participants with acute liver failure or severe acute liver injury. It describes intravenous infusion, a possible duration of up to 120 hours, and a 30 day follow-up visit. It also records serious and other adverse-event counts by maximum dose level and lists several serious adverse-event terms. Those details describe the study and its reported safety information.

The record does not report the numerical result for the primary safety endpoint. It also does not report statistical analyses for the listed secondary outcomes of plasma concentration, ammonia, or neurological function. The study hypotheses about tolerability, drug concentrations, ammonia, and neurological status are not findings. The available information therefore cannot quantify the primary endpoint’s frequency, estimate changes in secondary outcomes, or show how precise any treatment-related effect might be.

The single-group design further limits interpretation. Without randomized controls, observed events cannot be compared with outcomes under an alternative treatment strategy. The maximum-dose group counts are not a randomized dose comparison, and the record does not describe how participants reached those dose levels. Consequently, differences in the listed counts cannot be attributed to dose on the basis of these entries alone.

These limitations do not mean the study provides no useful information. Descriptive safety data and the study’s outcome framework can help readers understand what was monitored. But the registry record is not sufficient to establish the treatment’s causal safety profile or effects on ammonia and neurological function. No treatment recommendation follows from these statistics. Any broader interpretation would require results and methods that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable for the difference between a clearly stated safety question and the information available to answer it. The primary endpoint combines dose intolerance with grade 3 or 4 treatment-emergent adverse events, a more specific definition than a count of all adverse events. Yet its numerical result is not reported in the registry record. This illustrates why an outcome’s definition and its result both matter: knowing what was intended to be measured does not reveal what was observed.

The study also illustrates the role of design in interpretation. A single-group safety study can describe events among treated participants, which is relevant in an early-phase setting. Without random assignment to a comparator, however, it cannot isolate treatment effects from the underlying acute illness or other influences. The dose-level groupings add descriptive detail but do not create a randomized comparison. This distinction is especially important when reading adverse events and deaths in a population with serious liver injury.

Another statistical lesson is the importance of analysis transparency. The record lists several secondary outcomes but zero analyses, and does not report inferential results, confidence intervals, or missing-data methods. Without these details, readers cannot assess precision, evaluate how outcomes were analyzed, or understand how the planned questions relate to any reported conclusions.

Finally, registry entries can support careful description without supporting causal claims. The adverse-event counts are useful as recorded observations, while the absence of the primary endpoint result and analysis details limits what can be concluded. Recognizing both the information present and the uncertainty left unresolved is central to responsible statistical reading.

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 main limitation is that the primary endpoint result is not reported in the registry record. The endpoint is described, as is its 30 Days timeframe, but no count of participants meeting the combined safety definition is given. No confidence interval or inferential analysis is reported. This prevents assessment of the endpoint’s observed frequency and precision.

The single-group design has no randomized comparator, and the record identifies no masking. The dose-level categories are not described as randomized assignments. The rules for reaching or being assigned to a maximum dose level are not reported in the registry record, so dose-group comparisons may not be interpreted as causal or like-for-like comparisons.

Important detail about safety data is also absent. The record does not report event timing, duration, recurrence, causality assessments, causes of death, or the definition of the other-adverse-event category. It does not explain the denominator for the listed serious-event percentages or whether a participant could contribute to multiple terms. The serious-event entries do not substitute for the primary endpoint’s combined intolerance and grade 3 or 4 definition.

For the secondary outcomes, results and analysis methods are not reported. The registry does not provide measurement schedules, baseline definitions, approaches to missing measurements, or subgroup analyses for renal function. It lists zero analyses and does not describe multiplicity handling or analysis populations. Although 47 participants were enrolled, outcome-specific denominators are not reported. These limitations constrain both descriptive and inferential interpretation; they do not establish what analyses may exist outside the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury — NCT01548690.
• Registry record last updated 2018-10-30; status last verified 2018-10.
• Results first posted 2018-09-20.
• 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

NCT01548690 is a completed Phase 2a, single-group study of intravenous ornithine phenylacetate in acute liver failure or severe acute liver injury. The registry lists 47 enrolled participants, no masking, and no randomized allocation. The intervention description allows infusion for up to 120 hours, followed by a 30 day follow-up visit.

The primary safety endpoint was the number of participants who did not tolerate the administered dose and had grade 3 or 4 treatment-emergent adverse events, with a 30 Days timeframe. The numerical primary endpoint result is not reported in the registry record. The record lists adverse-event counts across four maximum-dose levels and secondary outcomes for plasma concentration, ammonia, and neurological function, but lists zero analyses.

The posted information supports a descriptive account of the study and recorded safety events. It does not provide a randomized comparator, an analyzed primary result, or reported statistical effects for the secondary outcomes. Therefore, it does not establish causal treatment effects or the precision of outcome estimates.