Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid (NCT04309656), a randomized phase 1 study. The primary outcome is Relative Bioavailability - Cmax.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, 4-period, 4-treatment crossover study. The record describes 2 panels of healthy adult participants and lists an enrollment of 48. It reports the study as completed, with a start date of 2020-01-14 and primary completion date of 2020-02-28. The sponsor was the Global Alliance for TB Drug Development.

In a crossover design, participants receive more than 1 treatment condition over separate periods. Each participant in this study was scheduled to receive 4 single doses, with a 7-day washout between doses. Panel 1 received a meal before dosing, whereas Panel 2 fasted before dosing. The study was open-label, so masking was not used according to the registry record. Randomization was reported, but the treatment sequence and the method used to generate or conceal assignments are not reported in the registry record.

The stated objectives included relative bioavailability, food effect, and dose-dependence for single-dose immediate-release and dispersible pretomanid formulations. The primary endpoint description identifies Cmax and says relative bioavailability was to be determined separately for each panel. Secondary outcomes include fed-versus-fasted ratios for Cmax, AUC from time 0 to t, and AUC from time 0 to infinity, as well as overall adverse-event incidence. The registry record does not give the dose amounts, exact treatment sequence, or detailed formulation-by-period schedule. Those details therefore cannot be used to interpret which treatment contrasts were actually estimated.

The crossover structure can be useful for pharmacokinetic comparisons because measurements from the same participant across treatment periods can be related to one another. As a general design consideration, interpretation depends on the treatment sequence, adequate washout, and handling of period or sequence effects. The registry record reports a 7-day washout but does not report how these design features were incorporated into the statistical analysis.

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: Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles

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 Relative Bioavailability - Cmax, measured over intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose.

The primary endpoint was relative bioavailability assessed using Cmax, the maximum observed concentration of pretomanid in plasma after dosing. The record specifies a mean as the summary measure and standard deviation as the measure of dispersion, with concentration expressed in ng/mL. Blood sampling was scheduled before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dosing.

Cmax is used in pharmacokinetic studies to describe the peak concentration reached during the sampling period. It is distinct from measures such as AUC, which summarize exposure over time. Comparing Cmax across formulation or food conditions can therefore address differences in peak concentration, but does not by itself describe the entire concentration-time profile or establish a clinical effect.

The record says relative bioavailability was to be determined separately for each panel. However, it does not report the actual Cmax means, standard deviations, treatment contrasts, or confidence intervals. The endpoint definition is available, but the posted results do not provide the numerical primary estimates needed to assess their magnitude or precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a continuous primary measure: Cmax, summarized by its mean and standard deviation. General statistical explanation can clarify what those summaries would convey, but the record does not include the observed means or standard deviations. No numerical treatment effect or uncertainty estimate can therefore be interpreted.

What does the mean describe?

In general, the mean is a measure of the central value of a set of observations. For a pharmacokinetic endpoint such as Cmax, it summarizes the observed peak concentrations for the analysis group. The mean alone does not show how widely individual observations vary, whether values are skewed, or how precisely the mean is estimated. The standard deviation describes the spread of observations around the mean; it is not the same as a confidence interval for the mean or for a treatment contrast.

The primary endpoint description reports mean and standard deviation as the planned summaries and gives ng/mL as the unit. It does not provide those numerical summaries in the registry record. It also does not state whether the primary comparisons used arithmetic or geometric means, whether values were transformed, or what contrast scale was used. Those analysis details are not reported in the registry record and should not be inferred from common pharmacokinetic practice.

Why does the crossover design matter?

In general, a crossover study measures participants under more than one treatment condition, allowing treatment comparisons to account for the fact that measurements from the same participant may be related. This can make a within-participant contrast more informative than a comparison that treats all observations as unrelated. The benefits depend on the design and analysis being appropriate, including consideration of period effects, treatment sequence, and possible carryover from an earlier period.

The record describes 4 treatment periods and a 7-day washout between single doses. It does not report the treatment sequences or the statistical model used to analyze the crossover data. It is not reported in the registry record whether period, sequence, or participant effects were modeled, or how any incomplete treatment sequences were handled. A design label alone does not establish which model was used.

How should confidence intervals be understood?

In general, a confidence interval expresses uncertainty around an estimate under the assumptions of the statistical method. For a treatment contrast, it can show which contrast values are reasonably compatible with the observed data and model. A confidence interval does not state the probability that a particular fixed value is true, and it does not by itself determine clinical importance. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed.

What do the sampling times contribute?

The endpoint was assessed using samples collected before dosing and at the scheduled post-dose times through 96 hours. In general, repeated concentration measurements help characterize the concentration-time profile and identify the observed maximum within the sampling schedule. Cmax is still a summary of that profile, not a complete description of exposure. AUC outcomes, also named in the registry record, summarize exposure across time in a different way. The registry record does not give their estimates or the methods used to derive or compare them.

What can be said about planning calculations?

General sample-size illustrations based on an observed effect are planning exercises: they show how a hypothetical future study might be sized under stated assumptions. They are not observed power and do not establish the design rationale for the completed study. The registry record does not report a sample-size justification, target power, or the assumptions used when planning the trial. No planning result can replace the missing primary endpoint estimates or uncertainty measures.

The record’s primary outcome is described as involving multiple categories or time points and is not reduced to a single comparison in the posted results. It reports 7 outcome measures and 6 analyses, but does not provide enough detail to map each analysis to a specific endpoint, treatment contrast, or model. The statistical methods used for the primary analysis, including any adjustment for multiple comparisons, are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The study includes multiple treatment conditions, a fed panel and a fasted panel, and several stated outcomes. The primary endpoint concerns Cmax, while secondary outcomes include fed-versus-fasted ratios for Cmax and two AUC measures, along with overall adverse-event incidence. Testing or estimating many outcomes can raise multiplicity questions, because repeated statistical tests can increase the chance of at least one apparently unusual result. General approaches include prespecifying a primary contrast, controlling an error rate, or treating secondary analyses as descriptive. The registry record does not report which approach, if any, was used.

The record lists 7 outcome measures and 6 analyses. It does not specify the full hierarchy of endpoints, which comparisons were confirmatory, or whether multiplicity adjustments were made. Since primary estimates and associated uncertainty are not reported, the impact of any multiplicity strategy cannot be evaluated from the registry record.

Information about missing data and analysis populations is also limited. The primary endpoint description says quantifiable predose concentrations below 5% of the respective Cmax values were included in pharmacokinetic analyses without adjustment. It further states that data for subjects with quantifiable predose concentrations above 5% of the respective Cmax values were excluded from concentration-time des—; the registry description is truncated at that point, and the remaining handling is not reported in the registry record. The record does not explain how missing post-dose samples, incomplete periods, or other exclusions were handled.

The record does not report a complete analysis-population definition, the number included in each endpoint analysis, or whether all randomized participants were analyzed under a particular population rule. Enrollment is not the same as the number contributing to every pharmacokinetic estimate. These omissions limit assessment of selection, missingness, and the relationship between the enrolled group and the analyzed data.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry record lists serious adverse events for each panel-and-treatment entry. For every listed entry, the number of participants at risk is 24 and the number affected by a serious adverse event is 0. Deaths are also listed as 0 for every entry, and no serious-event terms are listed.

Because this was a crossover study, the treatment entries refer to periods of treatment within panels rather than separate independent groups throughout the trial. The repeated at-risk entries should not be added to infer a trial-wide number of distinct participants. The record’s serious-event listings indicate that no serious adverse events or deaths were recorded in those entries; they do not establish that no non-serious adverse events occurred.

The registry record also gives non-serious adverse-event counts by treatment entry, ranging from 1 to 9. These counts are not serious-event counts and should be kept separate when reading the safety information. The record does not provide event descriptions, exposure-adjusted rates, or a detailed account of how events were attributed to treatment. As a result, the listings offer a limited descriptive view rather than a full comparative safety analysis.

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

This study is relevant to understanding the pharmacokinetic questions posed for single-dose immediate-release and dispersible pretomanid formulations. It used a randomized crossover design, separated dosing by a 7-day washout, and divided participants into fed and fasted panels. The primary endpoint was Cmax, with additional planned outcomes addressing food-related ratios for Cmax and AUC. These design and endpoint details clarify the scope of the investigation.

However, the registry record does not report the primary Cmax means, standard deviations, treatment contrasts, or confidence intervals. It also does not report the numerical results for the secondary food-effect outcomes or dose-dependence. Therefore, the posted results do not establish the direction, magnitude, or precision of the pharmacokinetic comparisons. No conclusion that a formulation or dosing condition produced higher or lower exposure can be drawn from the record’s study description alone.

In general, pharmacokinetic endpoints describe drug concentrations and exposure, not clinical benefit. Cmax concerns the peak concentration observed during sampling, while AUC summarizes exposure over time. Neither measure alone answers whether a treatment improves health outcomes. This study enrolled healthy adults and was described as a single-dose investigation; the registry record does not report clinical efficacy outcomes in people being treated for tuberculosis.

The serious adverse-event listings report 0 affected for each treatment entry and 0 deaths. These are descriptive registry entries, not a guarantee that every possible harm is absent, and they do not replace a full review of non-serious events or other safety information. The record’s limited safety detail and missing pharmacokinetic estimates should both be kept in view when interpreting what the trial can establish.

13. Why This Trial Matters Statistically

The trial raises statistical issues common in early pharmacokinetic studies: repeated treatment periods, correlated measurements within participants, food-related comparisons, and multiple outcomes. A crossover design makes the within-participant structure central to analysis. The treatment contrast, its uncertainty, and the handling of period and sequence effects are therefore important to interpreting any estimated relative bioavailability.

Food effects are expressed in the registry outcomes as ratios for Cmax and AUC measures. Ratios can be useful for comparing exposure across fed and fasted conditions, but interpretation requires the actual estimates and their uncertainty. Those results are not reported in the registry record. The design identifies the intended comparison, but the numerical evidence needed to judge its precision is absent.

The record also illustrates why endpoint definitions and results must be read separately. It specifies a mean Cmax, a standard deviation, a concentration unit, and a sampling schedule, yet those details do not reveal the observed values. Without estimates, confidence intervals, or a description of the analysis model, readers cannot assess the scale of the observed variation or the strength of the treatment comparisons.

Finally, the study’s healthy-adult, single-dose setting defines the scope of its evidence. Its pharmacokinetic objectives may inform how formulation and food conditions are studied, but the registry record does not report clinical outcomes or provide the results needed to quantify exposure differences. The statistical importance of this trial lies in the questions its design addresses and in recognizing the limits imposed by unreported analyses.

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 most consequential limitation for statistical interpretation is that the registry record does not report the numerical primary endpoint results. Means, standard deviations, treatment contrasts, confidence intervals, and p-values for Cmax are absent. The listed secondary food-effect outcomes and dose-dependence objective also lack numerical results. This prevents assessment of effect magnitude and precision.

Important analysis details are not reported in the registry record. These include the treatment sequence, the statistical model, handling of period or sequence effects, the complete analysis-population definitions, and the treatment of missing pharmacokinetic samples or incomplete periods. The record’s description of predose concentration handling is truncated, so its full implications cannot be assessed.

The trial was open-label, and masking was reported as none. The record does not explain whether the endpoints were measured or analyzed with any safeguards against knowledge of treatment assignment. It also does not report a multiplicity strategy despite the presence of multiple outcomes and comparisons. These omissions limit evaluation of potential bias and the reliability of any unreported comparisons.

The study was described as a single-dose investigation in healthy adults. The record does not report clinical efficacy results, and findings from this setting cannot be read as evidence about clinical outcomes in people with tuberculosis. The registry record also provides limited safety detail beyond event counts by treatment entry. These constraints apply alongside the missing pharmacokinetic estimates; they do not imply that unreported analyses had any particular result.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid — NCT04309656.
• Registry record last updated 2024-07-24; status last verified 2024-07.
• Results first posted 2024-07-24.
• 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

NCT04309656 is a completed Phase 1, randomized, open-label, 4-period crossover study of single-dose pretomanid in healthy adults. The registry record lists an enrollment of 48 and describes fed and fasted panels, with a 7-day washout between doses.

The primary endpoint was relative bioavailability assessed using mean Cmax in ng/mL, with standard deviation as the dispersion measure. The record also names food-effect ratios for Cmax and AUC outcomes, dose-dependence, and overall adverse-event incidence. Numerical primary and secondary pharmacokinetic results are not reported in the registry record, so their magnitude and precision cannot be assessed. Serious adverse events and deaths are listed as 0 for each treatment entry.