Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19 (NCT05166876), a randomized phase 2 study. The primary outcome is Safety and Tolerability of the Brequinar-dipyridamole Combination in COVID-19 Subjects.

2. Clinical Question

The trial’s primary focus was safety and tolerability, not a demonstrated antiviral or symptom benefit. Its listed secondary outcomes concern SARS-CoV-2 levels, time to symptom improvement, hospital admission or readmission, medical-attended visits, and supplemental support such as oxygen. Those questions are distinct from the primary safety endpoint. The registry record does not provide posted analysis results for those secondary outcomes in the registry record for this analysis.

The registry describes the study as randomized, assessor-blind, multicenter, and placebo-controlled in its official title; it also records triple masking and a parallel design. The precise identities of the masked groups are not reported in the registry record. The question that can be answered from the primary results is therefore narrow: whether any participants had the specified serious or higher-grade events considered related to treatment during the stated Day 29 timeframe. The zero counts describe the observations; they do not establish that the treatments have no safety risks.

3. Trial Design

This was a Phase II randomized, parallel-group study of brequinar, brequinar combined with dipyridamole, and placebo in participants with mild to moderate COVID-19. The registry records enrollment of 26 participants. The posted arm counts are 7 for brequinar monotherapy, 6 for placebo, and 13 for the brequinar-dipyridamole combination. The study status is terminated. The reason for termination is not reported in the registry record.

The official title describes an assessor-blind, multicenter, multi-dose, placebo-controlled study. The registry also lists triple masking. Which groups or study personnel were masked is not reported in the registry record, so the two masking descriptions cannot be reconciled from the available information. The record lists the study start as 2022-02-01 and primary completion as 2022-06-04.

The arm descriptions state that brequinar capsules were to be given once daily for 5 days using a dose-escalation approach, with planned doses of 50 mg, 100 mg, 150 mg, and 200 mg. The brequinar monotherapy and placebo descriptions say dosing would start at 50 mg and escalate if cohort stopping rules were not met. The combination-arm description is incomplete in the registry record, so its full dosing details cannot be established from that description. The record lists dipyridamole 75 MG as an intervention.

The primary endpoint was a participant count at Day 29. The registry record does not report the randomization method, allocation concealment procedures, the rationale for the planned enrollment, or a protocol-based sample-size justification. It also does not report how many participants completed follow-up or how many were included in each analysis population.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: No subjects experienced any grade 3 or 4 toxicity (related adverse event) or serious adverse event (SAE), therefore no analyses could be conducted.

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 Safety and Tolerability of the Brequinar-dipyridamole Combination in COVID-19 Subjects, measured over Day 29.

The primary endpoint is a count of participants with specified safety events by Day 29. It concerns grade 3 or 4 toxicities and serious adverse events considered by the investigator to be related to the combination, brequinar alone, or placebo alone. The posted results report zero participants with the endpoint in each of the three arms.

Safety endpoints are used to describe adverse events observed during a trial and to identify whether events meet prespecified or recorded criteria such as severity, seriousness, and relationship to treatment. These are different classifications: an event may be serious because of its consequences or management, while toxicity grade describes severity. The endpoint description combines grade 3 or 4 toxicity with serious adverse events considered related to treatment. The registry record does not provide further operational definitions or adjudication details.

With no observed endpoint events in any arm, the event counts do not support a meaningful estimate of a between-arm difference for this binary outcome. In general, an event-free observation in a small study does not prove that an event cannot occur; it only records what happened among the participants observed. The record states that frequencies could not be compared. It does not report a statistical test or an uncertainty interval for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary endpoint, each participant either meets the event definition or does not. The primary endpoint is reported as a participant count, and its event counts are zero in all arms. The relevant summaries are therefore the observed counts within the reported arm sizes: 0 of 7 for brequinar monotherapy, 0 of 6 for placebo, and 0 of 13 for the combination. These descriptions restate the posted values; they do not add a statistical estimate.

What does a between-arm comparison require?

In general, a comparison of binary outcomes uses the event frequency in each arm and expresses the contrast with an estimate such as a difference or ratio. An uncertainty interval can show how much imprecision accompanies that estimate. A statistical test can assess how compatible the observed data are with a specified null hypothesis. These are general concepts, not methods reported as having been used in this trial. The registry record says frequencies could not be compared and reports no primary analyses, test, effect estimate, or confidence interval.

When no events occur in any arm, the observed event frequencies are all zero. That pattern supplies no observed separation between groups for the endpoint. It also does not imply that the underlying event probabilities are known exactly. With limited observations, rare events can remain unobserved. Statistical methods for sparse binary data may be considered in other settings, but the registry record does not identify a method for this study, and no method-specific estimate should be inferred.

What does a confidence interval add?

Generally, a confidence interval communicates uncertainty around an estimated quantity, under the assumptions of the method used. It is not a guarantee that the true value lies within a particular interval, nor does a wide interval mean that treatments are equivalent. No interval is posted for the primary endpoint. Since there is no estimable event-frequency comparison in the record, there is no reported interval from which to judge the precision of a treatment contrast.

How should a p-value be interpreted?

In general, a p-value measures how unusual data at least as extreme as those observed would be under a stated statistical model and null hypothesis. It does not measure the probability that the null hypothesis is true, and it does not measure clinical importance. No p-value or hypothesis test for the primary endpoint is reported in the registry record. The absence of such a result is consistent with the record’s statement that the event frequencies could not be compared.

What do the planning assumptions mean?

The sample-size assumptions describe a planning illustration based on a stated fraction of the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. In general, sample-size planning asks how many participants per arm would be needed to detect a specified effect under chosen assumptions. Such a calculation is a planning illustration, not an observed trial result and not observed power. The registry record does not report a protocol-based sample-size justification. With the primary endpoint’s zero counts and no estimable two-arm comparison, the record does not support interpreting a planning calculation as evidence about the trial’s ability to detect a safety difference.

Over-dispersion is a general issue when the variability in data exceeds what a statistical model assumes. It can affect standard errors and the reliability of uncertainty estimates. It is not identified as an issue in this registry record, and the binary primary endpoint results do not report a model that could be assessed for over-dispersion. No model or adjustment should be attributed to the trial without a reported analysis.

The registry provides no analysis details for adjustment for baseline variables, handling of repeated measurements, or analysis populations. The lack of posted analyses means these features cannot be evaluated from the primary results. The main statistical conclusion is limited to the observed counts and the registry’s statement that the primary event frequencies could not be compared.

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("Brequinar Monotherapy", "Placebo", "Brequinar-Dipyridamole Combination")
n      <- c(7, 6, 13)
events <- c(0, 0, 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  Brequinar Monotherapy  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Placebo  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Brequinar-Dipyridamole Combination  13  0  0.0  0.0  24.7  0.0  22.8  0.2  23.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists five secondary outcomes: SARS-CoV-2 levels measured using qPCR through Day 29 at specified visits, time to symptom improvement, hospital admission or readmission, medical-attended visits, and supplemental support such as oxygen. It also records six outcome measures and five posted secondary outcomes. The results for those secondary outcomes are not reported in the registry record.

When a trial examines several outcomes or several comparisons, multiplicity is a general concern: the chance of at least one apparently notable result can increase as more statistical questions are tested. Researchers may address this through a prespecified testing order or adjustment, but neither an approach nor an analysis plan is reported in the registry record. The number of posted analyses is 0, so no multiplicity procedure can be assessed from the results.

Missing-data handling, participant exclusions, and analysis populations are not reported in the registry record. It is not stated whether the primary result uses all randomized participants, participants who received treatment, or another population, nor how absent Day 29 assessments were handled. The arm counts describe participants reported for each arm, but do not establish completion of follow-up or the denominator used for every outcome. These omissions limit assessment of how the observed counts relate to the full randomized population.

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 primary endpoint records zero participants with grade 3 or 4 toxicity or serious adverse events considered related to treatment in each arm by Day 29. The registry states that none of these events occurred, so frequencies could not be compared. This is a report of observed events, not a demonstration that serious or higher-grade events are impossible.

The separate serious adverse event summaries also show 0 affected participants among 7 at risk in the brequinar monotherapy arm, 0 among 6 in the placebo arm, and 0 among 13 in the combination arm. Deaths are reported as 0 in each arm. Other adverse events are reported for 1 participant in the monotherapy arm, 3 in the placebo arm, and 3 in the combination arm. The registry record does not provide event terms for those other events in the registry record, or state that they were related to treatment.

In general, zero events in a limited group leave uncertainty about events that might occur in a larger or differently observed population. These counts should be read alongside the stated arm sizes and the Day 29 timeframe, not as proof of no risk. The registry record does not report longer-term safety results or further details about the completeness of safety follow-up.

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

The results establish that the registry reports no primary endpoint events by Day 29 in any of the three arms. They also report no serious adverse events and no deaths in those arms. Other adverse events were observed, with the posted participant counts differing across the arms. These registry entries describe the reported trial observations; they do not, by themselves, establish a causal difference among treatments.

The primary endpoint comparison is not estimable in the posted results because there were no events in any arm. The record explicitly says that frequencies could not be compared, and it reports no analyses. There is no posted effect estimate, confidence interval, or p-value for the endpoint. It is therefore not possible to use this result to claim that the treatment groups have the same safety profile, or that one has a lower event frequency.

The trial’s primary question is distinct from its secondary questions about viral levels, symptoms, hospitalization, medical-attended visits, and supplemental support. Results for those outcomes are not reported in the registry record. The safety counts do not answer whether viral levels changed, whether symptoms improved sooner, or whether healthcare use differed.

The record identifies the study as terminated, but does not report why it was terminated. It also does not report the analysis populations, missing-data approach, or details of follow-up beyond the primary endpoint’s Day 29 timeframe. Those gaps matter when interpreting how fully the posted counts represent the randomized participants.

In general, a small number of observed participants can leave substantial uncertainty, particularly for uncommon events. The zero counts are not proof of absence of risk, and they should not be extended beyond the participants, endpoint definition, and follow-up described in the record. No treatment recommendation follows from these registry results.

14. Why This Trial Matters Statistically

This trial illustrates a basic challenge in safety analysis: a study can observe no events of interest yet still be unable to make a useful comparative estimate. The primary endpoint counts are zero in all arms, and the registry explicitly states that frequencies could not be compared. That is a statistical limitation of the observed data, not evidence that the arms are equivalent.

The three-arm structure is also important to interpretation. The study included brequinar monotherapy, placebo, and brequinar combined with dipyridamole. The posted arm sizes were 7, 6, and 13 participants, respectively. A reader should distinguish the combination question from the monotherapy and placebo arms rather than treating the study as a simple two-group comparison.

The trial’s listed secondary outcomes address different clinical and statistical questions, including viral levels and healthcare use. Since their results are not reported in the registry record, those questions cannot be answered from the primary safety counts. The contrast between a broad list of intended outcomes and the absence of posted analyses underscores the importance of transparent outcome reporting.

Finally, the record labels the study terminated but does not state a reason. Without that context, the status alone cannot explain the available results or establish whether termination affected follow-up or analysis. The registry record is useful for identifying what was measured and what was posted, while also making clear where comparative evidence is unavailable.

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 primary endpoint had no observed events in any arm, so the registry reports that frequencies could not be compared. This prevents estimation of a comparative effect from the posted primary results. The arm sizes were 7 for brequinar monotherapy, 6 for placebo, and 13 for the combination, limiting how much the observed zero counts can establish about uncommon events.

The registry record does not report a protocol-based sample-size justification, randomization procedure, allocation concealment, or the identities of the masked groups. It records triple masking and an assessor-blind design description, but does not explain their implementation. The reason for the terminated status is also not reported.

Further limitations include the absence of posted analyses, uncertainty about the analysis populations, and no reported handling of missing Day 29 assessments. Results for the listed secondary outcomes are not reported in the registry record. The combination-arm description is incomplete, and additional operational definitions for the safety endpoint are not reported. These gaps constrain interpretation of both the treatment comparisons and the completeness of outcome reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19 — NCT05166876.
• Registry record last updated 2023-11-07; status last verified 2023-10.
• Results first posted 2023-02-06.
• 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

This Phase II randomized parallel-group study examined brequinar monotherapy, brequinar combined with dipyridamole, and placebo in participants with mild to moderate COVID-19. The registry records 26 participants enrolled and lists the study as terminated. The official title describes a multicenter, multi-dose, assessor-blind, placebo-controlled study; the registry also lists triple masking.

The primary safety endpoint was a participant count by Day 29 for grade 3 or 4 toxicity or serious adverse events considered related to treatment. The posted count was zero in each arm, and the registry states that event frequencies could not be compared. It reports zero serious adverse events and deaths in each arm, as well as other adverse-event counts of 1, 3, and 3 across the monotherapy, placebo, and combination arms. No primary analyses are reported. Results for the listed secondary outcomes are not reported in the registry record.