Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19 (NCT04372628), a randomized phase 2 study. The primary outcome is Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group).

2. Clinical Question

The trial asks whether early outpatient treatment with lopinavir/ritonavir is associated with a different clinical-status outcome by Study Day 15 than placebo among adults with COVID-19. The registry describes a randomized, triple-masked, placebo-controlled trial and identifies the day 15 measure as a Modified COVID Ordinal Outcomes Scale. The score ranges from death at the lower end to being alive, not hospitalized, without symptoms, and without limitations in daily activities at the higher end.

The treatment group received lopinavir/ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses over Days 1-14. The control group received unmatched placebo orally twice daily for 14 days. The primary outcome timeframe is Day 1 to Day 15. The registry describes the primary outcome population as all randomized participants and says that “Unknown” represents participants with no daily surveys submitted over the first 15 study days.

The central statistical question is not simply whether participants were hospitalized or not. The ordinal scale distinguishes several levels of status, including hospitalization with different levels of respiratory support, being at home with symptoms and activity limitations, and being at home without symptoms or limitations. A comparison should therefore account for the ordered categories and their clinical severity, rather than treating every participant as belonging to a single undifferentiated event category.

The registry record does not report the day 15 distribution by treatment group, an estimated treatment contrast, a confidence interval, or a p-value. It therefore does not establish from the posted outcome data how the groups compared. The primary question is identifiable from the registered endpoint, but its statistical answer is not reported in the registry record.

3. Trial Design

The record identifies NCT04372628 as a phase 2 randomized trial titled “Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19.” Its official title names the study TREAT NOW. The condition listed is COVID-19, and the brief description characterizes the study as a blinded, multicenter, placebo-controlled, randomized clinical trial evaluating lopinavir/ritonavir in early outpatient treatment of adults with COVID-19. Vanderbilt University Medical Center is listed as sponsor.

The design fields identify the allocation as randomized, masking as triple, and model as sequential. The registry does not identify which three groups of people were masked, describe the randomization procedure or allocation ratio, or explain how the sequential model operated. Those details are not reported in the registry record, so the labels alone do not establish how those design features were implemented.

The trial lists lopinavir/ritonavir 400 mg/100 mg and placebo as interventions. The active regimen was oral dosing twice daily for twenty-eight doses (Days 1-14); the control regimen was unmatched oral placebo twice daily for 14 days. The posted enrollment is 452. Enrollment is not itself a result for the primary endpoint and does not indicate how many participants posted usable day 15 outcome information.

The start date is 2020-06-01, the primary completion date is 2021-12-16, and the status is completed. The primary endpoint is the Modified COVID Ordinal Outcomes Scale on Study Day 15, with the stated timeframe Day 1 to Day 15. The record also names secondary outcomes covering ordinal status on Study Day 8 and Study Day 29, hospitalization, time to hospitalization, symptom resolution, mortality, oxygen-free days, and fever-free days. Their presence in the registry does not establish that results were posted for them.

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: Includes all randomized participants, Unknown represents those with no daily surveys submitted over the first 15 study days

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.

Population: No difference in overall number of baseline participants and those assigned to study arms.

6. Primary Endpoint

The registry lists the primary outcome as Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group), measured over Day 1 to Day 15.

The primary endpoint is the Modified COVID Ordinal Outcomes Scale on Study Day 15. It is intended to represent clinical status across a range from death to being not hospitalized with no symptoms and no limitation in activities of daily living. The registry says the scale was modified from the COVID-19 WHO ordinal outcomes score to fit the outpatient setting. Lower scores indicate more severe outcomes, while higher scores indicate milder outcomes.

The categories distinguish death; hospitalization on mechanical ventilation or extracorporeal membrane oxygenator (ECMO); hospitalization on supplemental oxygen; hospitalization without supplemental oxygen; being not hospitalized with symptoms and limitation in activity; being not hospitalized with symptoms but without limitation in activity; and being not hospitalized without symptoms or limitation in activity. This structure allows the endpoint to distinguish degrees of severity that a single yes-or-no measure, such as hospitalization, would not capture.

In general, an ordinal outcome is useful when categories have a meaningful order but are not necessarily equally spaced. A move between adjacent categories cannot automatically be assumed to represent the same amount of change at every point on the scale. Interpretation therefore depends on the analysis method and on how the category distribution is reported. The statistical analysis method for this endpoint is not reported in the registry record.

The registry defines the population as all randomized participants and notes that “Unknown” represents those with no daily surveys submitted over the first 15 study days. No category counts or treatment-group comparison for the endpoint are reported in the registry record, so the observed day 15 clinical-status pattern cannot be described from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

The registry identifies this study as randomized. In general, random allocation is intended to make treatment groups comparable at the point of assignment, including with respect to factors that are measured and factors that are not measured. It supports a causal comparison when allocation is implemented as intended and when outcome collection and analysis are handled appropriately. Randomization does not guarantee that the groups will be identical, particularly in a finite study, and it does not remove the need to examine missing outcome information or deviations from the planned analysis.

The record does not describe the randomization sequence, allocation concealment, allocation ratio, or the statistical adjustment plan. These implementation details are not reported in the registry record. The posted enrollment of 452 describes the study’s enrollment, but does not reveal the number of participants included in a particular endpoint analysis.

How should triple masking be understood?

The masking field is listed as triple. In general, masking is intended to reduce the chance that knowledge of assigned treatment affects care, reporting, measurement, or interpretation. The exact people or roles masked, and whether masking was maintained throughout follow-up, are not reported in the registry record. The placebo is described as unmatched, but the record does not explain whether participants or study personnel could distinguish the treatment assignments.

Why does the ordinal scale matter?

The primary measure orders outcomes by severity, with death at score 1 and the least severe listed state at score 7. The categories are not just two alternatives: they distinguish levels of hospitalization, respiratory support, symptoms, and limitations in daily activities. General statistical practice treats such data as ordered categories; it does not assume automatically that each step represents an equal numerical distance. An analysis may compare the full distribution or use a model that makes assumptions about how the ordered categories relate across groups. The registry record does not identify the model, its assumptions, or a treatment-effect summary.

The outcome is measured at Study Day 15 within a timeframe labeled Day 1 to Day 15. The record says the outcome includes all randomized participants and defines “Unknown” for those with no daily surveys during the first 15 study days. It does not report how the unknown status was incorporated into the primary analysis. General methods for missing ordinal outcomes can make different assumptions; those assumptions can affect estimates and uncertainty.

What would an effect estimate and interval tell readers?

General statistical explanation: an effect estimate condenses the comparison between randomized groups according to a chosen measure. A confidence interval communicates uncertainty around that estimate under the analysis model. For an ordinal outcome, the meaning of the estimate depends on the model and whether it represents a distributional shift, odds across ordered categories, or another contrast. A p-value addresses compatibility with a specified null hypothesis under model assumptions; it does not measure the size or clinical importance of an effect.

None of these primary comparison quantities is reported in the registry record. No numerical treatment contrast, confidence interval, test statistic, or p-value can therefore be interpreted. The absence of a reported result is not evidence of no difference and is not evidence of equivalence.

What do the planning assumptions mean?

The statistical material associated with the record describes sample-size illustrations as planning calculations based on the observed effect, rather than the trial’s own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is to give the total number of events using the Schoenfeld method; for other outcomes, it is participants per arm.

These are planning illustrations, not observed power and not evidence that the trial was designed around a particular detectable effect. The record does not report the trial’s sample-size justification or establish that these illustrative assumptions were used to plan enrollment. Because the primary comparison and its observed effect are not reported in the registry record, the illustrations should not be treated as an independent estimate of the trial’s result.

What can be learned from the secondary outcomes?

The registry names outcomes at other time points and measures related to hospitalization, symptoms, mortality, oxygen use, and fever. In general, these outcomes can provide complementary information, but each has its own definition, timing, and analysis requirements. Time-to-event outcomes, for example, require methods that account for when an event occurs and how follow-up ends. The registry does not report statistical methods or results for these outcomes. It lists 13 outcome measures and 0 analyses, so no secondary-outcome treatment comparison can be interpreted from the posted record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary day 15 ordinal outcome and multiple secondary outcomes, including ordinal status at other study days and measures of hospitalization, symptom resolution, mortality, oxygen-free days, and fever-free days. It reports 13 outcome measures and 0 analyses. The record does not describe a multiplicity procedure, a hierarchy for testing outcomes, or which outcomes were intended to support confirmatory conclusions. Those details are not reported in the registry record.

General statistical context: when several outcomes or time points are tested, the chance of at least one apparently unusual result can increase if each test is interpreted without accounting for the broader testing plan. Methods such as prespecified hierarchies or adjustments can address this issue, but the appropriate interpretation depends on what was planned and which analyses were conducted. No multiplicity approach can be identified from the posted registry information.

The primary outcome population is described as all randomized participants. Participants with no daily surveys submitted over the first 15 study days are represented as “Unknown.” The number of participants with unknown status, the amount of missing survey data, reasons for missingness, and the method used to handle missing data are not reported in the registry record.

General statistical context: missing outcome data can affect a comparison if the participants without observed outcomes differ systematically from those with observed outcomes, or if missingness relates to treatment or clinical status. An analysis that excludes missing outcomes, imputes values, or uses another approach relies on different assumptions. Since the registry does not report the approach or relevant counts, the potential impact of missing data cannot be quantified.

The record does not identify the analysis population actually used, protocol deviations, interim analyses, or a statistical analysis plan. These are not reported in the registry record; conclusions about them should not be inferred from the randomized design label or the total enrollment.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lung infection (0.5%), sepsis (0.5%), adult respiratory distress syndrome (ards) (0.5%), cardiac arrest (0.4%), multi-organ failure (0.4%).

The registry lists serious and other adverse-event counts among participants at risk. In the group labeled Group 2 - Lopinavir/Ritonavir, 221 participants were at risk for serious adverse events and 2 were affected; 221 were at risk for other adverse events and 203 were affected, with 1 death listed. In the Placebo Control Group, 227 were at risk for serious adverse events and 1 was affected; 227 were at risk for other adverse events and 211 were affected, with 0 deaths listed. A separate group labeled Group 1- Hydroxychloroquine has 4 participants at risk for each adverse-event category, 0 serious events, 2 other adverse events, and 0 deaths.

These are registry counts, not estimates of causal effects. “At risk” identifies the recorded group denominator for the listed safety category, while “affected” is the number recorded with an event. The record does not provide detailed definitions, event-level narratives, exposure-adjusted rates, or a comparative statistical analysis. The listed hydroxychloroquine group is distinct from the two treatment groups described in the trial summary; the registry does not explain this listing.

The record also lists serious-event terms with percentages: Lung Infection, Sepsis, and Adult Respiratory Distress Syndrome (ARDS) at 0.5% each; Cardiac Arrest and Multi-Organ Failure at 0.4% each; and Acute Kidney Injury at 0.4%. These percentages should be read as posted serious-event summaries. They do not establish that an intervention caused the events or provide a treatment-group comparison.

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

The registry record establishes the broad design and clinical question: a randomized, triple-masked, phase 2 comparison of oral lopinavir/ritonavir with placebo in an outpatient COVID-19 trial. It also defines a day 15 ordinal clinical-status outcome and describes the score’s ordered categories. These details help readers understand what the study was intended to compare and what kinds of clinical states the endpoint distinguishes.

The record does not report the primary outcome results. There is no posted day 15 category distribution, treatment-effect estimate, confidence interval, or p-value. Accordingly, it is not possible to say from this record whether the outcome distribution differed between the groups, how large a difference may have been, or how precisely a difference was estimated. It is also not possible to conclude that the groups were equivalent merely because the registry lacks an analysis result.

The listed secondary measures and safety counts do not fill this gap. The presence of an outcome in the registry is not the same as a posted result, and safety event counts are not a substitute for a clinical-status comparison. The registry’s safety summaries can be described as counts, but they do not establish causation or comparative risk.

General statistical context: interpretation of a randomized trial depends not only on its design but also on the analysis population, missing-data handling, outcome definition, statistical model, and uncertainty around the estimate. For this trial, important analysis details—including the model used for the ordinal endpoint, multiplicity handling, and the treatment of missing surveys—are not reported in the registry record.

The sound conclusion is therefore limited: the registry documents a study designed to evaluate early outpatient lopinavir/ritonavir against placebo and specifies a clinically ordered day 15 endpoint, but the posted record does not supply the primary statistical result needed to assess the comparison. No conclusion about treatment benefit, lack of benefit, or equivalence follows from the absence of that result.

13. Why This Trial Matters Statistically

This trial is statistically notable for its use of an ordinal outcome intended to capture a range of clinical severity in an outpatient setting. Rather than reducing status to a single event such as hospitalization, the Modified COVID Ordinal Outcomes Scale distinguishes death, levels of hospital care and respiratory support, and differing symptom and activity states among participants not hospitalized. That choice can preserve information about gradations in status, provided the analysis respects the ordered nature of the categories.

The record also makes visible a recurring distinction in trial interpretation: a registered question is not the same as a reported answer. The trial’s randomized, triple-masked design and its endpoint definition describe the intended comparison, while the absence of a reported analysis prevents assessment of its estimate and precision. Enrollment of 452 does not supply the missing endpoint distribution or analysis.

The endpoint description explicitly identifies “Unknown” for participants with no daily surveys submitted over the first 15 study days. That makes outcome ascertainment and missing-data handling relevant to interpretation. Without counts of unknown outcomes or the analysis approach, readers cannot assess how much information was available for the primary comparison or what assumptions would be needed to interpret it.

Finally, the record lists several secondary outcomes but reports 0 analyses. This highlights why the number of registered outcomes alone is not enough to establish which findings were analyzed or how multiple comparisons were handled. In general, prespecified analysis plans and transparent reporting help readers distinguish primary evidence from exploratory analyses. The registry record does not report those analysis details, so its statistical contribution is chiefly to document the design and the planned outcome framework.

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 primary limitation for statistical interpretation is that no primary outcome analysis is reported in the registry record. The day 15 ordinal category results, treatment contrast, uncertainty interval, and p-value are absent. The statistical analysis method is also not reported, preventing assessment of how the ordered scale was modeled or summarized.

The endpoint description identifies participants with no daily surveys submitted over the first 15 study days as “Unknown,” but the number affected and the approach to missing data are not reported. The analysis population actually used, handling of protocol deviations, and reasons for missing information are also not reported in the registry record. These omissions make it impossible to assess the completeness of endpoint ascertainment or the sensitivity of any result to missing-data assumptions.

The registry calls the design sequential and triple-masked but does not describe the operational meaning of the sequential model or identify the masked roles. The allocation procedure, allocation ratio, sample-size justification, interim analyses, and statistical analysis plan are not reported. No particular procedure or justification should be inferred from the design labels.

The secondary outcome list is broad, but the record reports 0 analyses. It does not give outcome results or describe a multiplicity plan. The safety record includes a group labeled hydroxychloroquine, although the trial summary describes lopinavir/ritonavir and placebo; the reason for this additional listing is not reported. The serious-event summaries also do not provide event narratives or a causal assessment.

These limitations concern what the registry record makes available. They do not, by themselves, establish how the trial was conducted or what its full study report may contain. Any assessment beyond the design and posted summaries would require information not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19 — NCT04372628.
• Registry record last updated 2024-02-28; status last verified 2024-02.
• Results first posted 2023-01-26.
• 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

NCT04372628 is a completed phase 2 randomized trial sponsored by Vanderbilt University Medical Center. Its listed start date is 2020-06-01 and its primary completion date is 2021-12-16. The registry describes a triple-masked, sequential, placebo-controlled study of early outpatient lopinavir/ritonavir for adults with COVID-19, with enrollment of 452.

The active regimen was lopinavir/ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses over Days 1-14; the control regimen was unmatched placebo orally twice daily for 14 days. The primary measure was the Modified COVID Ordinal Outcomes Scale on Study Day 15, with categories ranging from death to no symptoms or activity limitation while not hospitalized.

The record lists secondary outcomes and safety summaries but reports 0 analyses. No primary outcome comparison or statistical result is reported in the registry record. Details on the statistical model, missing-data handling, multiplicity, and sample-size justification are also not reported.