Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis (NCT00396084), a randomized phase 1, phase 2 study. The primary outcome is Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC).

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group Phase I and Phase II study, with no masking. The registry lists 70 participants as the enrollment. The study concerned early bactericidal activity in HIV-negative adults with initial episodes of sputum smear-positive pulmonary tuberculosis. The brief summary specifies adults aged 18–65 years with newly diagnosed pulmonary tuberculosis.

The arm descriptions list gatifloxacin 400 mg orally once daily for seven days, levofloxacin 1000 mg orally once daily for seven days, moxifloxacin 400 mg orally once daily for seven days, and two linezolid schedules: 600 mg orally once daily or 600 mg orally every 12 hours for seven days. The isoniazid arm is described as 300 mg orally once daily for seven days. The registry gives planned arm sizes of 10 subjects for each of the listed non-isoniazid schedules and 20 subjects for isoniazid.

There is an unresolved difference in how the record describes the study population for the primary endpoint. It lists six treatment schedules, while the endpoint description says aAUC was calculated for 10 subjects per treatment arm (n=40). The record does not explain which participants or arms are included in that endpoint statement. Its title includes isoniazid, while the official title names linezolid, gatifloxacin, levofloxacin, and moxifloxacin. This variation makes the study scope less straightforward to summarize from titles alone.

The study-drug period was seven days of monotherapy. The brief summary says volunteers stayed in hospital for 10 days, provided blood and saliva samples, returned for a final health check six weeks later, and received six months of standard tuberculosis treatment. The registry lists a start date of 2004-02-10, primary completion on 2007-11-23, and status as completed. A detailed schedule of assessments and the method used to generate the random allocation are not reported in the registry record.

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 113 adults with suspected pulmonary TB were evaluated for study participation. Forty-three were excluded because they did not meet the eligibility criteria, leaving a total of 70 patients.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The aAUC was calculated for 10 subjects per treatment arm (n=40).

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC), measured over Study drug administration duration - 7 days monotherapy.

The primary endpoint is titled “Sputum Bacillary Loads: Adjusted Area Under the Curve (aAUC).” It summarizes sputum colony-forming units (cfu) across each day of study-drug treatment. The record describes the result as a percentage of the expected area under the curve if log cfu did not change in response to the study drug. The timeframe is the seven-day period of monotherapy. The stated summary parameter is the mean, with standard deviation as the measure of dispersion.

Area under a curve is a way to summarize a sequence of measurements over time rather than focusing on a single day. In general, it can represent both the level of a measurement and its course during the observation period. Here, the adjusted scale relates the observed bacillary-load trajectory to a reference trajectory defined by no change in log cfu. Conceptually, a lower percentage would indicate a trajectory further below that no-change reference; the registry record does not report actual percentages, so the observed direction or size of any result cannot be described.

This type of short-term microbiological endpoint is used to characterize early changes during treatment. It is distinct from a clinical outcome measured over the full course of tuberculosis treatment. The registry record does not establish how a short-term aAUC result relates to later clinical outcomes, and it does not report the endpoint values, uncertainty estimates, or a prespecified threshold for interpreting a difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies a continuous primary outcome summarized by the mean and standard deviation. These choices describe a distribution using its center and spread. In general, the mean is the arithmetic average of the observations included in a group, and the standard deviation describes how dispersed those observations are around that average. A standard deviation is not the same as a confidence interval: it describes variability among observations, whereas a confidence interval expresses uncertainty about an estimated quantity under a statistical model. The primary endpoint's reported values and any confidence intervals are not reported in the registry record.

What does area under the curve represent?

In general, an area-under-the-curve measure combines information across repeated measurements over time. It is useful when the timing and trajectory of change matter, rather than only the value at one assessment. The record says that sputum cfu were considered for each day on treatment and that the adjusted area was expressed relative to an expected area under a no-change-in-log-cfu reference. It does not describe the measurement schedule in detail, the formula for the adjustment, or the treatment of measurements that were unavailable.

The adjustment gives the outcome a defined reference: the expected trajectory if log cfu did not change in response to study-drug administration. That can make a trajectory easier to express relative to a baseline concept, but the scale still needs its specific calculation and results for practical interpretation. Those calculation details and numerical results are not reported in the registry record. General interpretation of the scale should not be confused with evidence of an observed treatment effect.

Why is the mean only part of the interpretation?

A group mean can conceal differences in how individual measurements are distributed. The standard deviation offers a description of spread, but it does not by itself show the precision of a comparison or whether group distributions overlap. For inference about a treatment contrast, analysts commonly consider an estimated difference together with an uncertainty interval and the assumptions used to obtain it. The record does not provide those elements for the primary endpoint. No new estimates can be recovered from the outcome definition alone.

General statistical practice also distinguishes a descriptive comparison from a causal treatment estimate. Random allocation can support comparisons between assigned groups when the analysis follows an appropriate plan and missing outcomes and deviations are handled transparently. The record identifies randomized allocation, but does not report the randomization procedure, the analysis model, adjustment variables, or the population included in the primary analysis. It is therefore not possible to assess those aspects of the analysis from the registry record.

What does the parallel, open-label design imply?

In a parallel-group design, participants are assigned to a treatment schedule and outcomes can be compared across groups. Randomization is intended to make assigned groups comparable on average, although it does not guarantee balance in every characteristic, particularly in a study with small planned arm sizes. The arm descriptions give 10 subjects for each non-isoniazid schedule and 20 for isoniazid. Whether these planned numbers match the numbers analyzed for aAUC is not reported. The primary endpoint statement instead refers to 10 subjects per treatment arm (n=40), without explaining the relationship to all listed schedules.

Open-label means treatment assignment was not masked. For an objective laboratory measure such as sputum cfu, the relevance of awareness of assignment depends on how samples are collected, processed, and assessed. The record does not describe masking of laboratory personnel or other safeguards. It would not be appropriate to assume either that open-label status changed the endpoint measurements or that it had no influence.

What can be said about multiplicity?

The registry lists 21 outcome measures and 29 analyses. In general, examining many endpoints, time points, or comparisons can increase the chance of finding an apparently notable result by chance if the analyses are interpreted without accounting for the multiplicity. Statistical approaches to multiplicity can include prespecifying a primary comparison or adjusting inference across a family of tests. The registry record does not report whether such an approach was used, how the primary endpoint categories or time points were handled, or which comparisons were designated as primary for inference.

The record’s sample-size assumptions describe an illustrative planning calculation based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. However, no calculated planning values or specific effect fraction are reported in the record excerpt. Such planning illustrations are not observed power and do not substitute for the trial’s own design justification. A formal sample-size justification and the trial's statistical analysis plan are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures and 29 analyses. The primary outcome description refers to several categories or time points and is not reduced to one comparison. These features raise questions about how multiple analyses were organized, but the registry record does not report a multiplicity strategy, a hierarchy of endpoints, or which specific contrasts were designated as primary. It is therefore not possible to determine whether the reported inferential results, if any, were adjusted for multiple testing. No primary endpoint inferential results are reported in the record.

Missing-data handling is not reported in the registry record. The record does not describe the number of participants with a primary endpoint measurement, reasons for missing measurements, how incomplete sputum series were treated in an area-under-the-curve calculation, or whether any imputation method was used. The endpoint description states that aAUC was calculated for 10 subjects per treatment arm (n=40), while the arm descriptions list six schedules and the overall enrollment is 70. The record does not clarify how those figures relate to the analyzed population.

The analysis population is also not reported in the registry record. It is not clear whether the primary analysis followed randomized assignment, included only participants who completed the study-drug period, or used another definition. The record does not describe exclusions after randomization, treatment discontinuations, protocol deviations, or whether the primary analysis was adjusted for baseline bacillary load or other characteristics.

The listed planning assumptions refer to an illustrative sample-size calculation based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The trial’s own sample-size justification, assumptions about the primary outcome, and planned handling of interim analyses are not reported in the registry record. These omissions limit assessment of how the analyses were planned and how robustly the primary question was addressed.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s adverse-event listing reports no serious adverse events among the participants at risk in any listed treatment group. It gives 10 at risk and 0 affected for each of the gatifloxacin, levofloxacin, once-daily linezolid, twice-daily linezolid, and moxifloxacin groups. For isoniazid, it gives 20 at risk and 0 affected. These figures describe the registry’s serious-event fields; the record does not provide serious-event terms.

The record separately reports participants affected by other adverse events: 8 for gatifloxacin, 7 for levofloxacin, 8 for once-daily linezolid, 5 for twice-daily linezolid, 7 for moxifloxacin, and 7 for isoniazid. The corresponding at-risk figures are 10 for each of the first five groups and 20 for isoniazid. These are counts as recorded, not estimates of comparative risk. No calculations or comparisons among groups are reported.

Death values are not reported in the registry record. The serious-event listing should not be read as a complete account of all possible harms: the record does not provide event descriptions, severity gradations for the other adverse events, timing, relatedness assessments, or the method of collection. With a short, seven-day study-drug period, the displayed figures describe the reported safety information for this study, not the full safety profile of any drug.

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

This randomized study was designed to assess early changes in sputum bacillary load during seven days of monotherapy with several antibiotics or isoniazid in HIV-negative adults with sputum smear-positive pulmonary tuberculosis. The primary measure, aAUC, expresses the sputum cfu trajectory relative to an expected trajectory with no change in log cfu. The registry record establishes the study question and the intended outcome definition.

The record does not report the primary aAUC values, group means, standard deviations, treatment contrasts, confidence intervals, or p-values. It therefore does not show whether the bacillary-load trajectories differed across regimens, how large any differences were, or how precisely they were estimated. The absence of those data in the registry record should not be interpreted as evidence of no difference, nor as evidence that a difference occurred.

The endpoint concerns a short-term microbiological measure during study-drug administration. It is not the same as a result on symptoms, long-term disease control, relapse, or any other clinical outcome. The brief summary says volunteers would receive six months of standard tuberculosis treatment after the study-drug period, but the record does not report outcomes from that later treatment course. It does not establish how aAUC relates to those longer-term outcomes.

The record also describes secondary outcomes, including sputum mRNA clearance, sputum cytokine proteins, and pharmacokinetic measures. Results for sputum mRNA clearance rate and sputum cytokine proteins are explicitly described as pending. The record lists pharmacokinetic outcomes but gives no corresponding results in the information available. These omissions prevent a broader comparison of microbiological, inflammatory, or drug-exposure findings.

Finally, the endpoint population is not fully reconciled with the six schedules in the arm descriptions and the overall enrollment. Without an analysis population, missing-data approach, or detailed statistical plan, a reader cannot assess how endpoint measurements were selected or how uncertainty and multiple analyses were handled. The proper conclusion is limited: the registry describes a randomized early bactericidal activity study, but its record does not provide the primary outcome findings needed to judge the observed results.

13. Why This Trial Matters Statistically

Statistically, this study illustrates the distinction between a trial’s question, its planned outcome, and the results needed for interpretation. The registry specifies a continuous measure of sputum bacillary-load trajectory over the seven-day study-drug period and defines its reference in terms of no change in log cfu. That definition gives a reader a basis for understanding what was intended to be measured, even though numerical results are absent.

The study also involves multiple treatment schedules, including two linezolid dosing schedules and an isoniazid comparison. Comparing several arms can make the choice of estimand important: a reader needs to know which between-group contrast addresses the main question and how multiple comparisons are handled. The record lists 21 outcome measures and 29 analyses, but does not specify a multiplicity approach or identify one primary contrast. This makes it difficult to connect the broad study question to a single inferential claim.

Another statistical issue is the difference between enrollment and analysis populations. The record lists 70 enrolled participants, describes planned arm sizes, and states that the primary endpoint was calculated for 10 subjects per treatment arm (n=40). It does not explain how the endpoint population corresponds to all listed arms. Clear reporting of participant flow, outcome availability, and analysis-population definitions is important because these details inform how representative and precise an estimate may be.

Finally, this is an example of why a defined endpoint is not enough to assess evidence. Means and standard deviations, a clear treatment contrast, and measures of uncertainty are needed to understand the observed effect and its precision. Without those results and the statistical analysis details, the registry entry documents the study’s structure but cannot support a statistical conclusion about comparative early bacillary-load activity.

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 main limitation for interpreting this trial from the registry record is that the primary endpoint results are not reported. The aAUC definition is available, but no arm-specific values, variability estimates, treatment contrasts, confidence intervals, or p-values are given. Consequently, the magnitude and precision of the primary findings cannot be assessed.

The description of the endpoint population is difficult to reconcile with the treatment-arm list. The registry lists six schedules, including isoniazid and two linezolid schedules, but states that the primary measure was calculated for 10 subjects per treatment arm (n=40). The record does not explain which arms or participants this represents. The enrollment figure and the arm descriptions do not resolve that question on their own.

The outcome measure is described as an adjusted area under the curve, but the calculation details are not reported. The registry does not specify the measurement schedule, the adjustment procedure, handling of incomplete trajectories, or the analysis model. It also does not report the analysis population, missing-data methods, or whether any baseline measurements were used for adjustment.

The study was open-label, and the registry does not say whether laboratory personnel assessing sputum samples were masked to treatment assignment. The record also does not report a multiplicity strategy despite listing 21 outcome measures and 29 analyses. The protocol’s formal sample-size justification and detailed analysis plan are not reported in the registry record.

Finally, the primary endpoint concerns short-term bacillary-load measurements during seven days of monotherapy. The registry does not report longer-term clinical outcomes or how aAUC relates to them. The safety listing gives serious and other adverse-event counts, but not detailed event terms, timing, or relatedness assessments. These limitations constrain interpretation of both efficacy-related and safety information from the record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Early Bactericidal Activity of Linezolid, Gatifloxacin, Levofloxacin, Isoniazid (INH) and Moxifloxacin in HIV Negative Adults With Initial Episodes of Sputum Smear-Positive Pulmonary Tuberculosis — NCT00396084.
• Registry record last updated 2018-11-08; status last verified 2010-03-10.
• Results first posted 2009-06-25.
• 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 randomized, open-label, parallel-group Phase I and Phase II study of early bactericidal activity in HIV-negative adults with initial episodes of sputum smear-positive pulmonary tuberculosis. Enrollment is listed as 70. Treatment schedules included gatifloxacin, levofloxacin, moxifloxacin, two linezolid schedules, and isoniazid, with study-drug administration for seven days.

The primary endpoint was sputum bacillary-load aAUC, expressed as a percentage of the expected area under the curve if log cfu did not change. The registry does not report primary endpoint results or a treatment comparison. It lists 21 outcome measures and 29 analyses, but the statistical analysis plan, multiplicity approach, missing-data handling, and analysis population are not reported in the registry record. The endpoint population statement is not reconciled with all listed treatment schedules.

The safety listing reports zero serious adverse events in each group and gives counts for participants affected by other adverse events. Death values are not reported in the registry record. The study’s record supports description of its design and intended measurements, but does not provide the primary findings needed to assess comparative aAUC results.