Study Comparing the Safety and Efficacy of Cethromycin to Clarithromycin for the Treatment of Community-Acquired Pneumonia (CAP): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Comparing the Safety and Efficacy of Cethromycin to Clarithromycin for the Treatment of Community-Acquired Pneumonia (CAP) (NCT00336505), a randomized phase 3 study. The primary outcome is Clinical Cures in the Intent to Treat Population.

2. Clinical Question

Clinical response was classified as cure, failure, or indeterminate. Cure required improvement, return to the preinfection state, or lack of progression of pulmonary infiltrates, together with resolution of signs and symptoms present at enrollment. Failure included persistent or worsening signs or symptoms, a need for additional antibiotic treatment, a new pulmonary infection, progression on chest radiograph, or death due to pneumonia. An evaluation that was not possible was classified as indeterminate, and indeterminates defaulted to failure for analysis.

3. Trial Design

This was a phase 3, randomized, quadruple-masked, parallel-group study. Its official title describes a double-blinded, multicenter, multinational comparison in adults with community-acquired pneumonia. The sponsor was Advanced Life Sciences, Inc. The study is recorded as completed, with enrollment of 584. The recorded start was 2005-12 and primary completion was 2007-10.

Participants were assigned to cethromycin or clarithromycin. The official title specifies cethromycin 300 mg once daily and clarithromycin 250 mg twice daily. The registry record does not provide additional arm descriptions. Random allocation is intended to make treatment groups comparable, on average, with respect to factors that could affect outcomes. Masking is intended to limit the influence of treatment knowledge on care, assessment, or reporting. The record identifies quadruple masking, but does not specify which roles were masked.

The primary outcome was clinical cure in the Intent to Treat Population at the Test of Cure Visit. This population included subjects with confirmed community-acquired pneumonia who took at least one dose of study medication; subjects without a radiologist-confirmed chest X-ray for pneumonia were excluded from the efficacy populations. The registry also names bacteriologic cure outcomes in the Intent to Treat Population and the Per Protocol Clinically Evaluable Population.

The record does not report the randomization procedure, allocation concealment details, the operational definition of the per-protocol population, or the rationale for the planned enrollment. It also does not report the detailed statistical analysis plan. These omissions limit how fully the design and analysis decisions can be reconstructed from the registry record alone.

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: In each treatment arm, one subject was enrolled and randomized to a blinded treatment but discontinued from study prior to administration of the first dose of drug. Thus, while official enrollment totalled 584 subjects, only 582 were randomized and dosed with blinded study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intent to Treat Population is defined as all subjects with a confirmed diagnosis of community acquired pneumonia who took at least one dose of study medication. Subjects without a radiologist-confirmed chest X-ray for pneumonia were not included in the efficacy populations.

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 Clinical Cures in the Intent to Treat Population, measured over Test of Cure Visit, defined as 14-22 days after the first dose of study drug..

The primary endpoint is the number of participants classified as clinical cures in the Intent to Treat Population. Investigators assigned each subject a clinical response of cure, failure, or indeterminate at the Test of Cure Visit, defined as 14-22 days after the first dose of study drug. The outcome therefore combines clinical signs and symptoms with assessment of pulmonary infiltrates rather than measuring a laboratory result alone.

Cure required improvement, return to the preinfection state, or lack of progression of all pulmonary infiltrates, along with resolution of all signs and symptoms present at enrollment. Failure covered persistent or worsening symptoms, additional antibiotic use, a new pulmonary infection, radiographic progression, or death due to pneumonia. Indeterminate status applied when evaluation was not possible, including loss to follow-up, an adverse event, or a major protocol violation. Indeterminates defaulted to failure for analysis.

Clinical cure is used to express whether the clinical conditions specified by the study had been met by the assessment visit. The endpoint is clinically interpretable, but its meaning depends on the registry's definitions and the timing of assessment. The registry record does not report the number of cures, failures, or indeterminate outcomes by treatment group, nor an effect estimate or uncertainty interval. Thus, the endpoint definition is available, but the primary efficacy result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization assigns participants to treatment groups by a chance-based process. In general, this helps reduce systematic differences in measured and unmeasured characteristics at the time of assignment. It does not guarantee that the groups will be identical, especially for any particular characteristic. The registry identifies the study as randomized but does not report the sequence-generation method or allocation concealment details.

Masking is intended to reduce the risk that knowledge of assigned treatment influences behavior or outcome assessment. The record labels the study quadruple-masked, while its official title calls it double-blinded. It does not identify which people or roles were masked, or describe how masking was maintained. The labels can be reported, but the practical implementation cannot be assessed from the registry record.

The study used a parallel-group design: participants were assigned to a treatment group and evaluated in that group. The primary endpoint is binary at the participant level because the clinical response was categorized as cure, failure, or indeterminate, with indeterminates counted as failures for analysis. The registry reports the primary measure as a number of participants, not a continuous measurement. A comparison of binary outcomes can be presented with group counts and an effect estimate, such as a difference or ratio in event frequencies. Such estimates should be paired with uncertainty intervals to show their precision. The primary outcome comparison and its uncertainty are not reported in the registry record.

A confidence interval is a statistical range constructed by a method that, under its assumptions, has a stated long-run coverage property. In general, a narrower interval indicates greater precision, while a wider interval indicates more uncertainty. An interval does not remove design limitations or establish that an effect is clinically important. Because no primary-outcome interval is reported in the registry record, the precision of the clinical-cure comparison cannot be assessed from this record.

A p-value, when used, measures how incompatible observed data are with a specified statistical model and null hypothesis. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry record does not report a primary-outcome p-value or enough primary outcome data to reconstruct the comparison. The statistical test and any adjustment for covariates are also not reported in the registry record.

The registry defines the Intent to Treat Population as subjects with confirmed community-acquired pneumonia who took at least one dose of study medication. It also excludes subjects without a radiologist-confirmed chest X-ray for pneumonia from the efficacy populations. In general, an analysis population determines which participants contribute to an estimate and therefore shapes what question that estimate answers. The record does not report a complete accounting of participants assigned, treated, excluded, and analyzed in each group, or the reasons for any exclusions.

For the primary outcome, indeterminate responses defaulted to failure. This rule makes explicit how one form of unavailable or inconclusive clinical assessment was handled. It does not describe how every other possible missing measurement or protocol deviation was managed. The registry record does not report additional missing-data methods, sensitivity analyses, or imputation procedures.

Multiplicity arises when a study tests several outcomes, populations, time points, or treatment contrasts. In general, making many inferential comparisons can increase the chance of at least one apparently notable finding under a null setting; analysis plans may address this by prespecifying a primary comparison or adjusting inference. The record names bacteriologic cure outcomes in two populations, in addition to the clinical-cure primary endpoint, but it does not report a multiplicity strategy or a hierarchy of confirmatory tests. It also does not report whether interim analyses were planned or conducted.

Sample-size calculations are planning tools based on assumptions about the effect to detect, variability or event frequency, significance level, power, and allocation. The stated assumptions describe planning illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are not the trial's original design justification and are not observed power. The trial's own sample-size justification is not reported in the registry record. More generally, power is a design property under specified assumptions; it is not a measure of how persuasive a completed study's results are.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary clinical-cure outcome and lists bacteriologic cure outcomes in the Intent to Treat Population and the Per Protocol Clinically Evaluable Population. It does not report a testing hierarchy, multiplicity adjustment, or rules for interpreting several outcomes together. Without those details, the degree to which the analyses were intended as confirmatory or exploratory is not reported in the registry record.

The Intent to Treat Population is defined as subjects with confirmed community-acquired pneumonia who took at least one dose of study medication. Subjects without a radiologist-confirmed chest X-ray for pneumonia were excluded from the efficacy populations. The record does not give a full participant flow or group-specific analysis denominators for the efficacy endpoint. It also does not define the Per Protocol Clinically Evaluable Population beyond naming it for a secondary outcome.

Indeterminate clinical responses were counted as failures. The registry describes indeterminate status as an evaluation that was not possible, including loss to follow-up, an adverse event, or a major protocol violation. This rule is a stated handling approach for that category, but other missing-data procedures, sensitivity analyses, and methods for handling protocol deviations are not reported in the registry record.

The record does not report interim analyses, stopping rules, or a detailed statistical analysis plan. These omissions mean that the timing and full structure of statistical decisions cannot be reconstructed. The available outcome definitions clarify what was intended to be measured, but the missing analysis details and primary results limit assessment of multiplicity, missingness, and the populations contributing to efficacy estimates.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (1.4%), pneumonia (1.4%), atrial fibrillation (0.3%), cardiac failure congestive (0.3%), pericardial effusion (0.3%).

The registry reports serious adverse events and other adverse events as participant counts, with the number at risk in each treatment group. For serious adverse events, 13 participants were affected among 288 at risk in the cethromycin group, and 9 among 291 at risk in the clarithromycin group. For other adverse events, 55 of 288 participants were affected in the cethromycin group and 37 of 291 in the clarithromycin group.

These are descriptive counts. They do not provide an adjusted comparison, confidence interval, or test of whether the groups differ. The record does not describe the event-collection period or provide additional detail about how events were classified beyond the serious and other adverse-event groupings. Death counts are not reported in the registry record.

The registry also lists serious adverse-event terms and percentages: acute myocardial infarction and pneumonia at 1.4%, and atrial fibrillation, congestive cardiac failure, pericardial effusion, and empyema at 0.3% each. The listed terms are not broken down by treatment group in the record. They should therefore be read as reported event information, not as evidence of a treatment-specific pattern. Differences in counts alone do not establish causation or determine the clinical significance of an event.

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

The registry record establishes that a completed phase 3 randomized comparison of cethromycin and clarithromycin was conducted in adults with community-acquired pneumonia. It provides the intended doses, a clinical-cure endpoint definition, the endpoint assessment timing, the definition of the primary analysis population, and descriptive safety counts. These details help clarify what the trial set out to compare and how its primary outcome was classified.

The record does not report the clinical-cure outcomes by group, a comparative effect estimate, a confidence interval, or a primary-outcome significance test. The central efficacy question therefore cannot be answered from the posted results. Neither a favorable nor an unfavorable efficacy conclusion follows from the fact that the study was completed or that it enrolled 584 participants.

The safety counts show how many participants were recorded as affected in each group, but do not quantify the uncertainty of a between-group comparison. The listed serious adverse-event terms are not given by arm. No causal interpretation or broad safety conclusion can be drawn from these descriptive details alone.

In general, a trial result is interpreted by considering the estimated effect, its precision, the endpoint definition, the analysis population, and the design and analysis methods. Statistical significance, if reported, would not by itself establish clinical importance; absence of a reported test is not evidence that the groups were identical. Here, the registry record does not provide enough primary efficacy information to judge either the magnitude or precision of the treatment comparison. The trial's endpoint and design can be described, but its primary clinical result is not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates why a trial's design information and outcome results need to be read separately. Randomization, masking, a parallel-group structure, and a defined endpoint describe how a comparison was intended to be conducted. They do not reveal the result. Even with enrollment of 584 participants and completed study status, efficacy interpretation still requires the group-level endpoint data and an estimate of the treatment contrast.

The primary endpoint also illustrates how outcome definitions influence statistical interpretation. Cure combined clinical improvement with assessment of pulmonary infiltrates, while failure included several forms of clinical worsening and indeterminate assessments defaulted to failure. These rules make the endpoint operational, but they also determine which observations count as successes and failures. A reader needs the outcome counts and analysis details to understand the resulting comparison.

The registry names bacteriologic outcomes in more than one analysis population. This raises general questions about how outcome families and populations are prioritized and how multiplicity is handled. The multiplicity plan is not reported in the registry record, so the intended inferential role of those additional outcomes cannot be evaluated.

Finally, the safety record demonstrates the distinction between counts and comparative inference. Counts identify recorded participants affected, while an uncertainty estimate is needed to convey the precision of a group comparison. The posted serious-event terms are not arm-specific. Taken together, the record is useful for understanding the study's design and endpoint definitions, while also showing how missing efficacy results and analysis details constrain statistical conclusions.

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 trial-specific limitation of the registry record is that it does not report the primary clinical-cure counts or a treatment-effect estimate. Without those results, the clinical-cure comparison cannot be evaluated for direction, magnitude, or precision. The record also does not report a primary-outcome confidence interval or significance test.

The endpoint definition is detailed, including the rule that indeterminate responses defaulted to failure, but the number of participants classified as indeterminate is not reported in the registry record. The record does not provide a full participant flow by treatment group, the number of participants included in each efficacy analysis, or reasons for exclusions beyond the radiologist-confirmation criterion.

The registry names bacteriologic cure outcomes in the Intent to Treat Population and the Per Protocol Clinically Evaluable Population, but does not provide a definition of the latter population or the corresponding results in the registry record described. The statistical analysis plan, covariate-adjustment approach, multiplicity strategy, and any interim-analysis procedures are not reported in the registry record.

Safety information is limited to participant counts for serious and other adverse events and a list of serious-event terms with percentages. The terms are not presented by treatment group in the record, and deaths are not reported in the registry record. The event-collection period and inferential comparisons are also not reported. These limitations restrict assessment of both efficacy and safety from the registry record, even though the design, treatment regimens, and primary endpoint definition are specified.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study Comparing the Safety and Efficacy of Cethromycin to Clarithromycin for the Treatment of Community-Acquired Pneumonia (CAP) — NCT00336505.
• Registry record last updated 2010-02-26; status last verified 2010-01.
• Results first posted 2010-02-26.
• 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

NCT00336505 is a completed phase 3 randomized, quadruple-masked, parallel-group study sponsored by Advanced Life Sciences, Inc. It compared cethromycin 300 mg once daily with clarithromycin 250 mg twice daily for community-acquired pneumonia in adults. Enrollment was 584; the recorded start was 2005-12 and primary completion was 2007-10.

The primary outcome was clinical cure in the Intent to Treat Population at the Test of Cure Visit, defined as 14-22 days after the first dose. Indeterminate responses defaulted to failure. The registry also names bacteriologic cure outcomes in the Intent to Treat Population and the Per Protocol Clinically Evaluable Population.

Serious and other adverse-event counts are reported by treatment group, and serious-event terms with percentages are listed. Primary clinical-cure results, comparative efficacy estimates, and the detailed statistical analysis plan are not reported in the registry record.