Study to Assess Brincidofovir Treatment of Serious Diseases or Conditions Caused by Double-stranded DNA Viruses: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Assess Brincidofovir Treatment of Serious Diseases or Conditions Caused by Double-stranded DNA Viruses (NCT01143181), a na phase 3 study. The primary outcome is Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus.

2. Clinical Question

3. Trial Design

This was a multicenter, open-label phase 3 study of oral brincidofovir for serious diseases or conditions caused by double-stranded DNA viruses. The registry lists a single-group model, no masking, and allocation as not applicable. It records 210 participants enrolled and the study status as completed. The study start and primary completion are recorded as 2010-12 and 2012-12, respectively.

Participants received weight-based or fixed-dose BCV once weekly or twice weekly. The treatment description allows treatment for up to 3 months until clinical disease was resolved or stabilized and/or viral DNA by polymerase chain reaction testing was negative for 4 consecutive weeks, whichever was longer. These are treatment conditions stated in the registry summary; the record does not provide participant-level treatment duration or adherence information.

The registry describes dose rules that changed with protocol amendments. Under the first amendment, adults and adolescents aged 13 years or older received 200 mg or 300 mg twice weekly according to the difficulty of treating their disease, subject to a maximum total weekly dose of 4 mg/kg. Pediatric participants aged 12 years or younger received 4 mg/kg twice weekly. Under the second amendment, adults and adolescents received a maximum weekly dose of 200 mg, given as 200 mg once weekly or 100 mg twice weekly, subject to the 4 mg/kg weekly limit. Pediatric participants received a maximum of 4 mg/kg weekly, given as 4 mg/kg once weekly or 2 mg/kg twice weekly, with a maximum of 200 mg.

Because the study had no randomized control arm, its design describes outcomes during BCV treatment but does not establish a randomized treatment contrast. The registry record does not report further allocation procedures, a statistical analysis plan, or a sample-size justification. It also does not report how participants were distributed across dose regimens or amendments.

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: Only subjects who achieved a confirmed reduction in viral load for the primary dsDNA virus of ≥1 log10 copies/mL from baseline or to an undetectable level were included in this analysis.

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: This was an expanded access study with the primary objective of providing brincidofovir (BCV) to subjects with serious or life-threatening conditions caused by double-stranded DNA viral infections. All subjects enrolled received BCV for up to 3 months until their clinical disease was resolved or stabilized and/or viral DNA testing was negative for 4 consecutive weeks, whichever was longer.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus, measured over 3 months.

The primary endpoint was the number of subjects with a sustained and significant reduction in plasma viral load for the primary double-stranded DNA virus. The registry defines success as a confirmed decrease of at least 1 log10 copies/mL from baseline or a viral load that reached an undetectable level. Confirmation required the reduction to be maintained at the next assessment. The stated timeframe was 3 months.

Viral load is a laboratory measure of viral DNA in plasma. In general, a change from baseline can describe whether the measured amount moved in a specified direction, while requiring confirmation at a subsequent assessment makes the endpoint less dependent on a single measurement. Reaching an undetectable level is also included as a qualifying outcome in this endpoint definition. These are general features of how such a measure can be interpreted; they do not establish the size or reliability of an effect in this study.

The registry describes the endpoint as a proportion, but its population description says that only subjects who achieved a confirmed reduction were included in the analysis. That wording leaves the analysis denominator unclear: it does not state how many subjects were assessed for the endpoint or how participants who did not meet the reduction criterion were handled. The number meeting the criterion, the denominator, and any estimate of the proportion are not reported in the registry record. Consequently, the endpoint definition can be described, but its observed result cannot be interpreted from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies one primary outcome measure and records no analyses. That description should not be read as evidence that no analyses were conducted; it means that inferential analyses are not posted in the registry record. No statistical analysis plan, model specification, covariate adjustment, or method for estimating uncertainty is reported in the registry record. The outcome definition and design can be explained, but the calculations used for any sponsor analysis cannot be inferred.

What kind of outcome is this?

The primary measure is a participant count for a binary outcome: each participant either met the stated success criterion or did not, according to the endpoint definition. In general, a binary outcome can be summarized by the number meeting the criterion and the number evaluated, as well as the proportion represented by those counts. Here, the registry does not post the success count or the number evaluated. Its description of the analysis population also says that only subjects achieving a confirmed reduction were included, leaving the denominator unclear.

The rule for success combines two possible findings: a decrease of at least 1 log10 copies/mL from baseline, or a result at an undetectable level. It further requires confirmation at the next assessment. In general, a confirmation requirement is intended to distinguish a maintained change from a finding at only one assessment. The record does not specify how a missing next assessment would be classified or whether a participant could still count as a success through another rule.

What does uncertainty mean?

In general, a confidence interval gives a range of values compatible with the observed data under the assumptions of the statistical method. Its width reflects how much uncertainty remains about the estimated quantity. A p-value, when reported, measures how unusual the data would be under a specified null model; it does not by itself describe the size or clinical importance of an effect. Neither a confidence interval nor a p-value for the primary endpoint is reported in the registry record. Since even the endpoint count and denominator are absent, no independent estimate or precision assessment can be derived from the posted results.

The study has no randomized control group. In general, a within-group result describes the outcome among participants receiving the intervention, whereas a treatment contrast requires an appropriate comparator and a defined comparison. A change from baseline can be informative descriptively, but it does not alone distinguish a treatment-associated change from changes that could occur over time for other reasons. The registry does not report a comparative efficacy analysis.

How should planning assumptions be read?

The registry's sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They also state that the effect to detect is a specified fraction of the observed effect. These are assumptions for planning illustrations, not evidence that the single-group trial used a two-arm design. No actual planning counts are reported in the registry record, and the record does not state a sample-size justification for this trial. Any planning illustration should not be interpreted as observed power. In general, power is a design-stage property under specified assumptions; it does not measure the certainty of a result after data collection.

The planning assumptions distinguish participant counts per arm from total event counts for time-to-event outcomes. The primary outcome in this record is a binary participant count, not a time-to-event endpoint. The registry does not post a planning estimate tied to this primary endpoint. No recalculated result or discrepancy with a sponsor analysis is reported in the record, so no alternative calculation can be compared with a sponsor estimate.

What can the safety groupings show?

The safety record lists participants at risk and participants affected for serious and other events within dose categories. These are descriptive counts. In general, a count without a defined randomized comparator does not establish that one dose category caused more or fewer events than another. The categories are presented by weekly dose, and the registry does not describe a randomized assignment to them. No adjusted comparison or uncertainty estimate for the safety counts is reported.

The posted serious adverse event terms include percentages, but the record does not state a comparative statistical model for those terms. Such percentages should be read as registry-listed descriptive frequencies rather than as a controlled risk contrast. The death field is not populated with a count, so deaths cannot be treated as absent based on this record.

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("BCV (≤4 mg/kg/Week)", "BCV (>4 mg/kg/Week)", "BCV (≤200 mg/Week)", "BCV (>200 mg/Week)")
n      <- c(25, 28, 79, 28)
events <- c(15, 18, 39, 13)
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  BCV (≤4 mg/kg/Week)  25  15  60.0  38.7  78.9  40.7  76.6  40.6  76.6
ARM  BCV (>4 mg/kg/Week)  28  18  64.3  44.1  81.4  45.8  79.3  45.7  79.3
ARM  BCV (≤200 mg/Week)  79  39  49.4  37.9  60.9  38.6  60.2  38.6  60.2
ARM  BCV (>200 mg/Week)  28  13  46.4  27.5  66.1  29.5  64.2  29.4  64.3

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity strategy. It identifies one primary outcome measure, but does not describe whether other outcomes were tested, how any family of hypotheses was defined, or whether statistical significance thresholds were adjusted for multiple comparisons. The record lists no analyses. That does not establish that no analyses occurred; their methods and results are not reported in the registry record.

Handling of missing data is not reported in the registry record. In particular, there is no description of how missing viral-load assessments, missing confirmation assessments, withdrawals, or incomplete follow-up were handled for the primary endpoint. The outcome definition requires the reduction to be maintained at the next assessment, but the record does not explain what happened if that assessment was unavailable. No imputation method, sensitivity analysis, or missingness summary is reported.

The analysis population is also insufficiently specified. The registry says that only subjects who achieved a confirmed reduction were included in the analysis, but does not report the number included or how that restriction relates to the stated proportion. It does not identify an intention-to-treat population, a per-protocol population, or another analysis set. The enrolled total of 210 should not be assumed to be the endpoint denominator because the record does not say that all enrolled participants contributed to the primary analysis.

Interim analyses, stopping rules, and any adaptations based on accumulating data are not reported in the registry record. Nor does the record provide a statistical analysis plan that could clarify endpoint definitions, analysis populations, multiplicity, or missing-data decisions. These omissions limit the ability to reconstruct the inferential approach or judge whether the posted outcome reporting is complete.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: respiratory failure (20.0%), acute graft versus host disease (17.5%), diarrhoea (16.7%), pyrexia (16.7%), multi-organ failure (15.0%).

The registry lists safety information in dose categories: BCV at or below 4 mg/kg/Week, BCV above 4 mg/kg/Week, BCV at or below 200 mg/Week, and BCV above 200 mg/Week. For each category it gives the number at risk and the number affected by serious and other events. For the at-or-below 4 mg/kg/Week category, 30 were at risk for serious events and 27 were affected; 30 were at risk for other events and 30 were affected. For the above-4 mg/kg/Week category, the corresponding counts are 38 and 32 for serious events, and 38 and 37 for other events.

For the at-or-below-200 mg/Week category, the record lists 102 at risk and 80 affected for serious events, and 102 at risk and 101 affected for other events. For the above-200 mg/Week category, it lists 40 at risk and 35 affected for serious events, and 40 at risk and 40 affected for other events. These counts are descriptive and should be read within the listed categories, not as randomized comparisons. The record does not explain whether or how participants may appear across dose groupings.

The listed serious-event terms include respiratory failure at 20.0%, acute graft versus host disease at 17.5%, diarrhoea at 16.7%, pyrexia at 16.7%, multi-organ failure at 15.0%, and hypotension at 10.5%. The registry record does not provide a statistical comparison for these terms. Death counts are not reported in the registry record. These safety figures describe what is posted; they do not establish comparative risks.

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

The registry record documents a completed phase 3 study of oral brincidofovir in participants with serious conditions caused by double-stranded DNA viruses. It specifies a single-group, open-label design, dosing approaches, and a primary endpoint based on a confirmed reduction in plasma viral load. This information describes the study question and how success was defined.

The posted record does not include the primary endpoint result. It gives no number of participants achieving the criterion, no denominator for the stated proportion, and no confidence interval or p-value. The registry's population description further complicates interpretation because it says only subjects who achieved a confirmed reduction were included in the analysis. Without clarification and the underlying counts, the primary endpoint cannot be quantified or assessed for precision.

Even if a within-group viral-load change had been posted, the absence of a randomized comparator would remain important. A single-group design can describe findings among participants receiving BCV, but cannot establish how those findings compare with outcomes under a control treatment or no study treatment. The open-label design also means participants and study personnel were not masked according to the record. The registry does not report what influence, if any, this had on measurements or clinical decisions.

The safety record provides counts across dose categories and selected serious-event terms. These figures are descriptive; they do not supply a randomized comparison and should not be interpreted as proof that a dose category caused a different rate of events. Death counts and statistical safety analyses are not reported in the registry record.

Overall, the record supports a description of trial design, dosing, endpoint definition, and posted safety counts. It does not support a quantitative conclusion about the primary endpoint, its precision, or a causal treatment effect. That distinction is central: a stated endpoint and a completed study are not substitutes for a reported outcome estimate.

14. Why This Trial Matters Statistically

This study is statistically notable because its registry record combines a clearly specified virologic success rule with an incomplete account of the primary outcome. The endpoint requires a decrease of at least 1 log10 copies/mL from baseline or an undetectable result, confirmed at the next assessment. Such a definition identifies what was intended to count as success, but statistical interpretation also needs the number of successes, the number evaluated, and an estimate of uncertainty. Those outcome results are not reported in the registry record.

The analysis-population wording highlights why endpoint definitions and denominators must be considered together. The registry says that only subjects who achieved a confirmed reduction were included in the analysis, while describing the outcome as a proportion of subjects who achieved that reduction. Without clarification of which participants form the denominator, the proportion cannot be understood or reproduced. This is not a minor reporting detail: the denominator determines what population the estimate would describe.

The single-group design is another important statistical feature. It permits descriptive reporting of outcomes during treatment but provides no randomized control contrast. The dose categories listed for safety do not resolve that limitation because the record does not describe randomized allocation to those categories. Comparisons across groups with different dose levels would require additional design and analysis details that are not reported.

The example also illustrates that registry status, phase, and enrollment do not convey the strength or precision of an outcome result. Although the study is listed as completed and phase 3, the primary estimate and its uncertainty are absent from the posted record. Statistical transparency depends on reporting results and analysis populations, not only protocol features. Here, readers can identify what was measured and how success was defined, but cannot determine the observed primary outcome from the registry record.

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 limitation for interpreting efficacy is that the registry record does not report the primary endpoint result. There is no success count, analysis denominator, estimated proportion, confidence interval, or p-value. In addition, the endpoint population description says only subjects who achieved a confirmed reduction were included, which leaves the denominator and intended analysis population unclear.

The single-group, open-label design has no randomized control arm, and the registry itself cautions that dose groups are not a like-for-like control comparison. Consequently, the record does not provide a randomized estimate of a treatment contrast. Masking was listed as none. The record does not report whether clinical assessments were independently reviewed or whether any other procedures reduced the potential influence of open-label conduct.

Further trial details needed for a fuller statistical assessment are not reported in the registry record. These include a sample-size justification, statistical analysis plan, interim analyses, missing-data methods, analysis-set definitions, and methods for addressing multiplicity. The registry also does not clarify the endpoint denominator or how a missing confirmatory assessment was handled. Although enrollment is listed as 210, the number included in the primary analysis is not stated.

The safety data are grouped by dose categories and list participants at risk and affected, but the record does not explain the category assignment or whether participants could be represented in more than one grouping. It does not report adjusted safety comparisons, uncertainty estimates, or death counts. The posted serious-event terms and percentages therefore provide descriptive information only. These limitations constrain interpretation of both the primary endpoint and safety findings without establishing that any unreported analysis or procedure was absent from the conduct of the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Assess Brincidofovir Treatment of Serious Diseases or Conditions Caused by Double-stranded DNA Viruses — NCT01143181.
• Registry record last updated 2021-08-12; status last verified 2021-07.
• Results first posted 2021-08-12.
• 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 describes NCT01143181, a completed, multicenter, open-label phase 3 study of oral brincidofovir for serious diseases or conditions caused by double-stranded DNA viruses. It lists a single-group model, no masking, allocation as not applicable, and enrollment of 210. Treatment was given once or twice weekly using weight-based or fixed doses, with dosing rules that changed under protocol amendments.

The primary endpoint was a confirmed reduction in plasma viral load for the primary virus by at least 1 log10 copies/mL from baseline or to an undetectable level, maintained at the next assessment. Its timeframe was 3 months. The registry record does not report the endpoint result, analysis denominator, uncertainty estimate, or inferential analysis. Safety counts are posted by dose category, along with selected serious-event terms. These are descriptive and do not constitute randomized comparisons. The record does not report a sample-size justification, missing-data methods, multiplicity strategy, or statistical analysis plan.