Atovaquone and Azithromycin Combination for Confirmed COVID-19 Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Atovaquone and Azithromycin Combination for Confirmed COVID-19 Infection (NCT04339426), a na phase 2 study. The primary outcome is Virology Cure Rate.

2. Clinical Question

3. Trial Design

The registry record identifies this as a Phase 2 study of atovaquone and azithromycin for confirmed COVID-19 infection. Its official title describes an open-label, non-randomized study of anti-malarial/anti-infective combination therapies. The recorded model is single group, masking is listed as none, and allocation is listed as NA. In practical terms, the record does not describe randomized assignment or a blinded comparison. It also does not identify a concurrent control group.

The intervention is recorded as Atovaquone/Azithromycin. The regimen specifies atovaquone 750 mg PO Q12H for up to 10 days, and azithromycin 500 mg PO Day 1 followed by 250 mg PO daily for up to 10 days (Days 2-10). These details describe the intervention in the registry; they do not establish how consistently it was taken or whether every enrolled participant completed the regimen. Adherence and treatment exposure by participant are not reported in the registry record.

The study lists 3 participants enrolled and is marked terminated. The recorded start date is 2020-04-20, and the primary completion date is 2022-02-11. The registry record does not state why the study was terminated or explain the relationship between the recorded dates and participant follow-up. It lists 5 outcome measures and no analyses. The primary outcome is the virology cure rate, with a 10-day timeframe.

Because the design has one group and no randomized comparator, the study can describe outcomes among those enrolled if results are reported. It cannot, by design alone, separate an intervention-associated outcome from other possible explanations for what happened during the study. Details such as a prespecified analysis plan, sample-size justification, interim analyses, and a fuller description of follow-up 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.

Overall Study

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 Virology Cure Rate, measured over 10 days.

The primary endpoint is titled Virology Cure Rate and is defined as the percentage of patients who achieved an undetectable COVID-19 viral load via serology testing. The registry specifies a 10-day timeframe and describes the measure as a percentage of participants. This is a binary-outcome concept: each participant either meets the stated criterion or does not, and the summary measure is the frequency meeting it.

As a general statistical concept, a binary endpoint can offer a direct summary of how often a prespecified event occurs in a study population. A virologic measure may be used to capture a laboratory-defined outcome rather than a broader clinical change. The exact interpretation depends on the operational definition, measurement procedures, timing, and handling of missing test results. Those details, beyond the definition and timeframe stated above, are not reported in the registry record.

The registry record does not report a result for this endpoint. It therefore does not establish how many participants achieved the criterion, what percentage that represented, or how precise an estimate would be. No confidence interval or inferential analysis for the primary endpoint is reported. The endpoint definition alone is not an outcome result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary measure as a percentage of participants and describes the event as achieving an undetectable COVID-19 viral load via serology testing within 10 days. This is a binary endpoint: for each participant, the event is either recorded as achieved or not achieved under the stated definition. A percentage summarizes the proportion of the analyzed group meeting that definition. The registry record does not report the numerator, denominator used for the primary result, or an analysis of this endpoint.

As a general statistical concept, a point estimate is a single summary calculated from observed data. It is useful as a compact description, but it does not convey all the uncertainty that comes from observing a finite group. A confidence interval is a range calculated by a specified method to express uncertainty around an estimate. Its width depends on the data and the method. No primary endpoint estimate or confidence interval is reported in the registry record, so there is no precision estimate to interpret.

For a binary endpoint, analyses commonly distinguish participants who meet the event definition from those who do not. The denominator is important: it determines which participants contribute to the summary. If endpoint measurements are missing, different ways of handling them can change that denominator or the event classification. The registry record does not report the number with an available serology result, the handling of missing results, or an analysis population for the primary endpoint. No missing-data method is reported in the registry record.

As a general principle, a prespecified analysis plan helps clarify which outcome definitions, populations, and statistical methods will be used before results are known. The plan can also specify how uncertainty will be quantified and whether adjustments are needed when multiple outcomes are assessed. A statistical analysis plan, named hypothesis test, confidence-interval method, or model for this study is not reported in the registry record. No particular method should therefore be attributed to the investigators.

The study's design is also central to interpretation. It is recorded as single group, non-randomized, open-label, with no masking and allocation listed as NA. These characteristics mean the record does not establish a randomized treatment contrast. As a general concept, randomization can help create comparable groups for estimating a treatment contrast, while blinding can reduce some forms of influence on assessment or reporting. Neither feature is recorded for this study. An outcome in the enrolled group, even if reported, would remain a description of that group rather than a controlled estimate of a treatment effect.

The study lists 3 participants enrolled. General statistical precision is constrained by the amount of information in the data; small groups usually leave considerable uncertainty around estimated proportions. That general point does not justify calculating an interval or an event rate when the primary endpoint data are absent. The adverse-event denominators are separately recorded as 2 participants at risk for serious events and 2 at risk for other events; those figures should not be substituted for the missing primary endpoint denominator.

The record also includes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Such an illustration is a hypothetical planning calculation, not an observed result or evidence of observed power. Its assumed two-arm allocation does not match the recorded single-group design. The study's own sample-size justification and statistical design rationale are not reported in the registry record. No planning illustration can supply a missing primary outcome result or overcome the absence of a comparator.

Over-dispersion is a general concern when observed variability exceeds what a model assumes. It matters when the chosen statistical model relies on a particular variance structure, because underestimating variability can make uncertainty appear too small. The registry record does not report a model for the primary outcome or indicate whether over-dispersion was assessed. It would be inappropriate to infer that such a model or assessment was used.

The record lists 5 outcome measures and no analyses. That information does not establish which analyses were planned, completed, or omitted. The registry record also does not report interim analyses, adjustment for multiple outcome testing, or a rationale for the selected endpoint timeframe. Without those details and the primary endpoint data, the methodological interpretation is limited to the recorded design and outcome definition.

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("Atovaquone/Azithromycin")
n      <- c(2)
events <- c(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  Atovaquone/Azithromycin  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including the primary virology cure rate and secondary outcomes titled Incidence of Gastrointestinal Adverse Events and Cardiac Toxicity. It lists no analyses. The record does not report whether the outcomes were tested as separate hypotheses, whether one outcome was designated as the principal basis for inference, or whether any multiplicity adjustment was planned or used. The existence of several outcomes does not, by itself, reveal how the investigators intended to interpret them together.

As a general statistical concept, evaluating multiple outcomes can increase the chance that at least one result appears notable by chance if each is assessed independently. Methods for managing that issue depend on the questions and analysis plan. No such method is reported in the registry record. No p-values or inferential results are reported for the listed outcomes.

The registry record does not describe missing-data handling for the primary endpoint or secondary outcomes. It does not state how unavailable serology measurements, incomplete follow-up, or missing adverse-event information were treated. Nor does it define a primary analysis population, such as the participants included in an endpoint analysis. The enrolled count is 3, while the recorded adverse-event at-risk counts are 2 for serious events and 2 for other events; the reason for these denominators is not reported in the registry record.

These omissions make it difficult to determine which participants contributed to each outcome, whether the outcome data were complete, and how uncertainty should be evaluated. They should be treated as unreported methodological details, not filled in by assumption.

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 non-serious adverse event terms

The registry records 0 serious adverse events among 2 participants at risk for serious events. It also records 2 other adverse events among 2 participants at risk for other events. No deaths are recorded. These figures describe the counts and denominators entered in the registry; they are not a comparison between treatment groups.

The difference between the enrollment count of 3 and the recorded at-risk counts of 2 is not explained in the registry record. It is therefore unclear from the record which participants contributed to each safety count or why the denominators differ. The registry lists gastrointestinal adverse events and cardiac toxicity as secondary outcomes, but their outcome results are not separately reported in the information available for interpretation. The serious-event terms are also not listed.

As a general statistical concept, safety counts with small denominators provide limited precision about how often events might occur beyond the observed participants. A recorded count of zero does not establish that an event could not occur, and counts alone do not show whether an event was caused by an intervention. The registry's safety figures should be read as recorded observations, not as a definitive safety profile.

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

The record documents a Phase 2, open-label, non-randomized, single-group study of atovaquone and azithromycin for confirmed COVID-19 infection. It records 3 enrolled participants and defines a primary endpoint based on achieving an undetectable COVID-19 viral load via serology testing within 10 days. It does not report the primary endpoint result. Accordingly, the posted results do not establish the observed virology cure rate or the precision of an estimate.

Nor does the design provide a concurrent randomized comparison. A single-group result, if available, could describe what was observed among participants in that group, but could not by itself isolate the effect of the intervention from other explanations. This is an inference limitation, not a claim that the intervention did or did not affect an outcome.

The safety counts are also limited. The registry records 0 serious adverse events among 2 participants at risk and 2 other adverse events among 2 participants at risk, with 0 deaths. The record does not explain the safety denominators or report the named secondary outcome results in detail. Such counts in a small group cannot settle how frequently events would occur in a broader population.

The terminated status and absence of reported primary analysis leave important questions unanswered, including why the study was terminated, how endpoint data were handled, and whether outcome collection was complete. Those details are not reported in the registry record. The appropriate reading is therefore narrow: the record describes the intended endpoint, intervention, design, enrollment, and selected safety counts, while leaving the primary efficacy result and much of the analysis unavailable. It does not support a conclusion that the combination works or does not work.

14. Why This Trial Matters Statistically

This study illustrates why a clearly named endpoint is not the same as a reported endpoint result. The registry defines a virology cure rate using an undetectable COVID-19 viral load via serology testing and specifies a 10-day timeframe. Yet the record does not report the number of participants who met that definition or an estimate of uncertainty. For statistical interpretation, the distinction between an outcome definition and observed data is fundamental.

The record also shows how design determines the kinds of claims that are possible. A single-group, open-label, non-randomized study can describe outcomes among enrolled participants, but it does not provide a randomized contrast with a control group. This matters even when a numerical outcome is available: description of an observed group and estimation of a comparative treatment effect answer different questions.

The enrollment of 3 participants makes precision especially important to consider, while the absent primary result prevents even a limited estimate from being stated. The safety record includes at-risk denominators of 2, and the reason those differ from enrollment is not reported. Such details affect what can be inferred from counts and how confidently they can be generalized.

Finally, the record lists 5 outcome measures and no analyses. The absence of reported analysis methods, missing-data handling, or multiplicity procedures leaves uncertainty about how outcomes were intended to be interpreted. These are not reasons to assume an analysis was inappropriate; they are boundaries on what the registry record can substantiate. The study is statistically informative as an example of how design, outcome reporting, denominators, and analysis transparency shape interpretation.

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 principal limitation is that the registry record does not report the primary virology cure result. It therefore provides no observed event count, percentage, confidence interval, or inferential result for the primary endpoint. The outcome definition and timeframe alone cannot answer how many participants met the criterion.

The recorded design is single group, open-label, and non-randomized, with no comparator described. Any outcome from the group would be descriptive and could not establish a treatment contrast against a concurrent control. The record does not report a statistical analysis plan, sample-size justification, interim analyses, or the reason the study was terminated.

Enrollment was 3, but the serious-event and other-event at-risk denominators are each 2. The registry record does not explain the denominators or identify the participants included in the safety counts. It also does not report the outcome-specific denominators, missing-data procedures, or analysis populations for the primary and secondary outcomes. The gastrointestinal adverse event and cardiac toxicity outcomes are named, but their results are not reported in detail.

Further details about eligibility, participant characteristics, endpoint measurement procedures, adherence, follow-up completeness, and the handling of unavailable tests are not reported in the registry record. Without these details, readers cannot assess the comparability of the enrolled group to other populations or determine whether outcome ascertainment was complete. These limitations restrict interpretation of the record; they do not establish what the unreported results would have been.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Atovaquone and Azithromycin Combination for Confirmed COVID-19 Infection — NCT04339426.
• Registry record last updated 2026-06-29; status last verified 2024-12.
• Results first posted 2026-06-29.
• 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

The registry record describes a Phase 2, open-label, non-randomized, single-group study of atovaquone and azithromycin in patients with confirmed COVID-19 infection. It lists 3 participants enrolled, a start date of 2020-04-20, a primary completion date of 2022-02-11, and a terminated status.

The primary endpoint is the percentage of participants who achieved an undetectable COVID-19 viral load via serology testing within 10 days. Its result is not reported in the registry record. The record lists 5 outcome measures and no analyses. Safety entries include 0 serious adverse events among 2 participants at risk, 2 other adverse events among 2 at risk, and 0 deaths. The reason for termination and the explanation for the safety denominators are not reported.