Evaluation of TRC101 in Subjects With Metabolic Acidosis Associated With Chronic Kidney Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of TRC101 in Subjects With Metabolic Acidosis Associated With Chronic Kidney Disease (NCT03317444), a randomized phase 3 study. The primary outcome is Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range.

2. Clinical Question

The clinical question is therefore framed as whether assignment to TRC101 rather than placebo was associated with meeting this composite serum bicarbonate endpoint at Week 12. The two ways of meeting the endpoint are combined: a participant could qualify through the specified increase from baseline or through an end-of-treatment value in the stated normal range. Because the endpoint is a percentage of participants, it describes how many in the defined analysis population met at least one of those criteria, rather than the average change in bicarbonate for all participants.

The record identifies efficacy evaluation according to planned treatment assignment in the Modified Intent-to-Treat Analysis Set. It does not report endpoint results or details of a treatment-effect model. Consequently, the registry information characterizes the question and population but does not establish the direction, size, or precision of the treatment contrast. The outcome should not be read as a direct measure of every aspect of kidney disease or of participants’ overall health; it is specifically a serum bicarbonate endpoint measured over the stated period.

3. Trial Design

This was a phase 3, multicenter, randomized, parallel-group, placebo-controlled study with quadruple masking. Its official title describes a double-blind study; the registry separately classifies masking as quadruple. The record does not specify which groups of people were masked, so the masking label should not be expanded into assumptions about particular roles.

The study enrolled 217 participants. Its brief summary had anticipated approximately 210 adult male and female participants with stage 3 or 4 chronic kidney disease and metabolic acidosis. TRC101 and placebo were each administered once daily for 12 weeks. The maximum study duration was anticipated to be up to 16 weeks. The registry lists the start date as 2017-09-26, primary completion as 2018-05-04, and study status as completed.

Random allocation is intended to create groups that can be compared without choosing treatment on the basis of participant characteristics. In a parallel design, participants are assigned to one study arm and followed in that arm, rather than crossing from one treatment to another. Placebo provides the stated comparator for interpreting the endpoint under the trial conditions. These are general features of the design; the registry record does not provide the allocation sequence, concealment procedures, or operational details of masking.

The primary endpoint was assessed from baseline to Week 12. The primary outcome description defines a composite based on serum bicarbonate change or the end-of-treatment value. A secondary outcome is listed as change from baseline to end of treatment in serum bicarbonate. The record states that there were two outcome measures and four analyses, but does not identify all their details in the information recorded. The record does not report a protocol-level sample-size justification, planned allocation ratio, or full statistical analysis plan; those details should not be inferred from the enrollment or design labels.

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: The Modified Intent-to-Treat (MITT) Analysis Set was defined as all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using an i-STAT device. The MITT Analysis Set was used for evaluation of efficacy, based on planned treatment assignment.

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 Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range, measured over Baseline to Week 12.

The primary endpoint is a binary composite measured as a percentage of participants. A participant meets the endpoint if serum bicarbonate increases from baseline by at least 4 mEq/L, or if the Week 12 end-of-treatment serum bicarbonate is within the stated normal range of 22 - 29 mEq/L. The registry describes the measurement period as baseline to Week 12.

Combining criteria can capture more than one way of reaching a clinically interpretable biochemical target. The change criterion reflects movement relative to an individual participant’s baseline, while the range criterion uses the participant’s end-of-treatment value. This is a general description of why a trial might define a composite endpoint; the registry record does not state the rationale for choosing these particular criteria.

Because the endpoint is expressed as a percentage, its meaning depends on both the definition of success and the analysis population. The record defines the efficacy population as randomized participants with a baseline and at least one postbaseline serum bicarbonate measurement using an i-STAT device, analyzed according to planned treatment assignment. It does not report how many participants met the endpoint in either arm, the resulting percentage estimates, or a confidence interval. Nor does it report the component-specific results, which would be needed to distinguish how often each route to meeting the composite occurred. Without those outcome values, the endpoint definition can be interpreted, but its observed treatment contrast cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

The primary endpoint is a binary outcome at the participant level: each participant either meets the composite definition or does not. The group result is expressed as a percentage of participants. This differs from a mean change, which averages numerical measurements across people. A percentage can be useful when the question concerns the proportion reaching a prespecified state, but its interpretation depends on the exact event definition and the denominator used.

In this trial, either of two serum bicarbonate criteria qualifies. One is a change from baseline of at least 4 mEq/L; the other is a Week 12 value in the 22 - 29 mEq/L range. Combining criteria generally makes a composite endpoint broader than either component alone. As a general statistical consideration, component results can help readers understand what drives a composite. Those component-specific results are not reported in the registry record.

What does the confidence interval contribute?

The registry describes the primary endpoint dispersion as a 95% confidence interval. In general, a confidence interval gives a range of estimates compatible with the data under the method’s assumptions and conveys uncertainty around an estimate. It is not a guarantee that the true value lies within a particular interval, and it does not replace a clear statement of the estimated treatment contrast. The interval values are not reported in the registry record, so neither the estimated uncertainty nor the precision of the primary result can be assessed.

For a treatment comparison, interpretation usually depends on estimates for both arms or on a contrast between them, together with an interval and the analysis definition. The registry record does not give primary endpoint percentages, a contrast, or a p-value. No recalculated comparison can be described from the endpoint information recorded. The simple, unadjusted recalculations sometimes used to check posted summary results require posted numerical summaries; no such primary endpoint summaries appear in the registry record recorded for this trial.

How does the analysis population affect the result?

The registry defines the Modified Intent-to-Treat Analysis Set as randomized participants with both a baseline and at least one postbaseline serum bicarbonate value measured using an i-STAT device. Efficacy evaluation used planned treatment assignment. In general, an analysis population determines which participants contribute to an estimate and therefore what that estimate describes. A population defined by availability of measured follow-up values may differ from the full randomized population. The record does not state the size of this analysis set, how many randomized participants lacked qualifying measurements, or how missing measurements were handled.

Analyzing according to planned assignment preserves the randomized group labels for participants included in the stated population. As a general principle, this approach can retain the comparability created by randomization more directly than grouping participants by treatment actually received. It does not, on its own, resolve missing outcome data or explain exclusions from an analysis set. The registry record does not report additional details about adherence, treatment discontinuation, or sensitivity analyses.

Why does endpoint structure matter?

The registry information indicates that the primary outcome has several categories or time points and is not reduced to one comparison. This limits interpretation: a trial can have multiple reported outcome values or analyses, and choosing one contrast without a stated plan can be misleading. The registry record does not provide enough detail to identify a single primary numerical comparison, its model, or its estimate. No statistical method should be inferred from the phase, design, or endpoint label alone.

Multiplicity is a general concern when several outcomes, time points, or comparisons are tested. The more analyses considered, the greater the chance that at least one result may appear unusual by chance if no adjustment or prespecified hierarchy is used. The registry record does not report a multiplicity strategy or explain how the four analyses relate to the outcome measures. Therefore, whether and how multiplicity was addressed is not reported in the registry record.

What can the design and planning information establish?

Randomization and a placebo-controlled parallel design describe how the comparison was organized; they do not reveal the observed treatment effect. Enrollment was 217, whereas the brief summary anticipated approximately 210 participants. These figures describe enrollment and the earlier stated expectation, not the number analyzed for the primary endpoint or the precision of its estimate.

The general planning illustration described for sample-size calculations uses a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the target effect expressed as a fraction of an observed effect. Such calculations are planning illustrations, not observed power and not evidence of efficacy. They are not the trial’s own design justification. No resulting participant counts for the illustrations are reported in the registry record, and the primary outcome has not been reduced to a single comparison in the record. The protocol’s sample-size justification and full statistical plan are not reported in the registry record.

In general, over-dispersion matters when observed variability exceeds what a model assumes; underestimating that variability can make uncertainty appear too small. The registry information does not identify a count model or report over-dispersion diagnostics for the primary outcome. This concept therefore explains a general modeling issue, not a feature confirmed for this trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry record names the Modified Intent-to-Treat Analysis Set for efficacy. It consists of randomized participants who had a baseline and at least one postbaseline serum bicarbonate measurement using an i-STAT device, with evaluation based on planned treatment assignment. The number of participants in this set, and the number not included, are not reported in the registry record.

The record does not state how missing baseline or follow-up measurements were handled, whether any imputation was used, or whether sensitivity analyses assessed the effect of missing data. These details matter because a percentage endpoint requires a defined denominator and outcome classification. General statistical practice would distinguish participants with observed outcomes from those whose outcomes are unknown rather than assuming that missing values indicate either success or failure. No particular missing-data approach can be attributed to this trial from the registry information.

The primary outcome is described as having several categories or time points and is not reduced to one comparison. The registry lists two outcome measures and four analyses, but does not report the full mapping between them, the testing hierarchy, or an adjustment for multiple comparisons. Multiplicity refers generally to the challenge of interpreting multiple statistical tests or outcome comparisons: without a stated plan, selective emphasis on one result can make the overall evidence harder to assess. Whether an adjustment or prespecified hierarchy was used is not reported in the registry record.

The registry identifies a 95% confidence interval for the primary endpoint but gives no interval values, treatment contrast, or inferential results. It also does not report a complete statistical analysis plan. Thus, the analysis population is defined in broad terms, while missing-data procedures and multiplicity handling remain unspecified in the registry record.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: angina unstable (1.1%), diabetic hyperglycaemic coma (1.1%), pneumonia (1.1%), fall (0.8%), acute left ventricular failure (0.8%).

The registry reports serious adverse event counts by treatment arm. In the TRC101 arm, 3 of 124 participants at risk had a serious adverse event; in the placebo arm, 2 of 93 participants at risk had a serious adverse event. The record reports 0 deaths in the TRC101 arm and 2 in the placebo arm. These are descriptive counts, not a statistical comparison. The registry does not report a confidence interval or inferential test for these figures.

The record also lists the following serious adverse event terms and percentages: Angina unstable, 1.1%; Diabetic hyperglycaemic coma, 1.1%; Pneumonia, 1.1%; Fall, 0.8%; Acute left ventricular failure, 0.8%; and Cardiac failure congestive, 0.8%. The listed percentages should be read as registry-reported values; the record does not provide additional context about their arm-specific distribution.

The other adverse event counts are 31 of 124 participants at risk in the TRC101 arm and 13 of 93 in the placebo arm. These counts are distinct from the serious adverse event counts. Descriptive event totals alone do not establish a causal difference between arms, and they should not be used as a substitute for the primary efficacy results.

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

The registry record establishes that a completed phase 3 randomized, placebo-controlled study evaluated TRC101 and placebo in participants with chronic kidney disease and metabolic acidosis. It states the primary endpoint definition, its baseline-to-Week 12 timeframe, the planned treatment schedules, and the efficacy population definition. Those details clarify what the study set out to measure and how the registry characterizes the efficacy analysis.

The record does not report the numerical primary endpoint results. It therefore does not show the percentage meeting the composite in either arm, the size or direction of a treatment contrast, or the precision of any estimate. It also does not provide the component results that would distinguish participants meeting the change criterion from those meeting the end-of-treatment range criterion. The secondary outcome is named, but its numerical result is not reported in the registry record.

This means the registry information cannot establish whether the observed endpoint percentages differed or how reliably a difference was estimated. It would be inappropriate to interpret the absence of outcome values as evidence of no effect, or to infer an outcome from enrollment, study completion, design features, or adverse event counts. The data recorded support a description of the trial question and its methods, but not a conclusion about the primary efficacy result.

The serious adverse event and death counts provide a separate descriptive view of safety reporting. They are not, by themselves, a complete safety assessment or a formal comparison. The registry record does not report inferential uncertainty for those counts, and they do not answer the primary endpoint question.

In general, a trial result is best interpreted with its estimate, uncertainty, analysis population, and outcome definition considered together. Here, the endpoint and population are described, but the key numerical efficacy results and several analysis details are not reported in the registry record. The scope of any conclusion must remain limited to what the record actually states.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a registry can define a randomized comparison and a composite endpoint without supplying the numerical outcome results needed to interpret that comparison. The distinction between an endpoint definition and an endpoint estimate is fundamental: knowing what counted as success does not reveal how often success occurred or whether the arms differed.

The composite combines a participant-level change criterion with an end-of-treatment range criterion. That structure raises an interpretive question common to composite outcomes: a combined result may conceal variation in which component contributes to the total. Reporting component-specific estimates alongside the composite can make the result easier to understand. Those component estimates are not reported in the registry record.

The stated efficacy population also illustrates why analysis-set definitions matter. The Modified Intent-to-Treat Analysis Set requires a baseline and at least one postbaseline measurement. This is a concrete rule, but the number of participants meeting it and the treatment of missing values are not reported. Without those details and the endpoint values, readers cannot assess the analysis denominator or the robustness of the result to missingness.

The record reports study enrollment and a planned efficacy population definition, but enrollment is not a substitute for an endpoint estimate. It also identifies multiple analyses without reporting the multiplicity strategy. These omissions make it especially important not to infer statistical conclusions from design labels or descriptive safety counts.

More broadly, the case underscores that statistical interpretation depends on transparent reporting of the planned comparison, analysis population, missing-data approach, multiplicity handling, effect estimate, and uncertainty. The registry record supplies some of that framework but does not report enough numerical efficacy information to judge the primary contrast.

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.

A central limitation of the registry information is that it defines the primary composite endpoint but does not report the endpoint percentages, treatment contrast, confidence interval limits, or p-value. As a result, the efficacy effect and its precision cannot be assessed from the record. The description that the outcome has several categories or time points and is not reduced to one comparison further limits the ability to identify a single primary numerical contrast.

The component-specific results are not reported. Because either the change-from-baseline criterion or the end-of-treatment range criterion qualifies, the composite alone would not explain which component contributed to any observed result, even if a combined estimate were available. The record also does not report the number of participants in the Modified Intent-to-Treat Analysis Set or the number excluded from it.

Missing-data handling, sensitivity analyses, and details of the statistical model are not reported in the registry record. The record also does not specify a multiplicity approach despite identifying multiple analyses. The protocol’s sample-size justification and full statistical analysis plan are not reported. These gaps constrain assessment of the analysis and of how robust any result would be to alternative assumptions.

Safety information is limited to the counts and listed serious-event terms and percentages recorded. The registry does not provide inferential comparisons for these figures. The enrollment of 217 and the anticipated enrollment of approximately 210 do not resolve the missing efficacy results, and should not be mistaken for the number contributing to the primary endpoint analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of TRC101 in Subjects With Metabolic Acidosis Associated With Chronic Kidney Disease — NCT03317444.
• Registry record last updated 2021-04-26; status last verified 2021-03.
• Results first posted 2021-04-26.
• 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, multicenter, randomized, parallel, placebo-controlled study with quadruple masking. It enrolled 217 participants; the brief summary had anticipated approximately 210 adults with stage 3 or 4 chronic kidney disease and metabolic acidosis. TRC101 and placebo were each taken once daily for 12 weeks.

The primary endpoint was the percentage meeting a composite serum bicarbonate criterion from baseline to Week 12. Efficacy was defined for a Modified Intent-to-Treat Analysis Set based on availability of baseline and at least one postbaseline i-STAT measurement, analyzed by planned assignment. The primary endpoint values and treatment comparison are not reported in the registry record. Serious adverse event counts, other adverse event counts, and deaths are recorded descriptively, but no inferential safety comparison is reported.