Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246 (NCT00907803), a randomized phase 2 study. The primary outcome is Number of Study Participants Who Tolerated a Single Daily Oral ST-246 Dose as Determined by Safety Parameter Changes According to the DAIDS (Division of Acquired Immunodeficiency Syndrome) Adverse Events (AE) Grading Table..

2. Clinical Question

The study was designed to assess safety, tolerability, and pharmacokinetics for two clinical doses of ST-246 in volunteers receiving treatment in the fed state. Its stated purpose was to inform which dose would be used in expanded pivotal safety trials. The clinical question is therefore about tolerability and safety monitoring in this trial population, rather than treatment of orthopoxviral disease.

The posted primary outcome counts participants who met the registry’s definition of tolerating treatment. The registry reports 34 participants in the 400 mg group, 38 in the 600 mg group, and 15 in the placebo group. Those counts are interpreted alongside each group’s reported enrollment and the comparison estimates. They do not, by themselves, establish why a participant did or did not meet the tolerance definition.

The record describes safety monitoring that included adverse events, vital signs, physical examinations, laboratory tests, and electrocardiograms. It does not report an operational threshold defining tolerance beyond reference to safety-parameter changes and the DAIDS grading table. The registry also lists pharmacokinetic measures as secondary outcomes, including Cmax, Tmax, AUCtau, and t½.

3. Trial Design

This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 2 trial. The registry lists enrollment as 107 and the status as completed. The recorded start was 2009-06, and primary completion was 2010-01. Participants received ST-246 400 mg, ST-246 600 mg, or matching placebo, orally once daily for 14 days in the fed state.

The posted primary outcome counts were 34 of 45 participants in the 400 mg group, 38 of 46 in the 600 mg group, and 15 of 16 in the placebo group. These are the group sizes and outcome counts reported for the primary measure. The registry states that the primary outcome population was per protocol, but the rules for inclusion in that population are not reported in the registry record.

Outcome monitoring covered Days 1 to 14 and then 24, 48, 72, 96 and 120 hours and 4 weeks after the final dose. The safety measures named in the description were adverse events, vital signs, physical examinations, hematology, blood chemistry, urinalysis, and electrocardiograms. The primary measure was based on changes in safety parameters graded using the DAIDS adverse-event grading table.

The record describes six withdrawals. In the 400 mg group, the listed reasons were adverse events (2) and consent withdrawal (1). In the 600 mg group, the listed reasons were subject request (1), lost to follow-up (1), and protocol violation (1). These withdrawal descriptions do not establish how any missing measurements were handled in the analysis.

The registry lists pharmacokinetic parameters as secondary outcomes. The trial’s original sample-size justification, detailed randomization procedures, and full statistical analysis plan 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.

Before assignment: Following an up to 14-day Screening Period, eligible subjects were randomly assigned to receive either ST-246 400 mg (n=45) or ST-246 600 mg (n=46) or placebo (n=16). Treatment was orally administered after a light meal over a 14-day Treatment Period. There was a 28-day Follow-up Period.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: As per protocol. During the study, a total of 6 withdrawals occurred. These were due to adverse events (2) and consent withdrawal (1) in the 400 mg group, and subject request (1), lost to follow-up (1) and protocol violation (1) in the 600 mg group.

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 Number of Study Participants Who Tolerated a Single Daily Oral ST-246 Dose as Determined by Safety Parameter Changes According to the DAIDS (Division of Acquired Immunodeficiency Syndrome) Adverse Events (AE) Grading Table., measured over Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose.

The primary endpoint is the number of participants who tolerated a single daily oral ST-246 dose, as determined by changes in safety parameters according to the DAIDS adverse-event grading table. The registry describes safety monitoring across adverse events, vital signs, physical examinations, laboratory tests, and electrocardiograms. The outcome timeframe extends from Days 1 to 14 through scheduled assessments after the final dose, including 4 weeks after that dose.

This endpoint is used to summarize tolerability in the study’s volunteer population and to compare the observed counts across the dose groups and placebo. That focus matches the stated purpose of assessing safety and tolerability while evaluating two clinical doses. The registry says the trial results would inform dose selection for expanded pivotal safety trials; it does not state a specific decision rule for that selection.

The reported counts were 34 participants in the 400 mg group, 38 in the 600 mg group, and 15 in the placebo group. The registry does not provide a more detailed operational definition of what qualified as tolerating treatment, such as a specified threshold or a rule for combining safety findings. Consequently, the outcome should be read according to the registry’s stated description, not as a broader measure of clinical benefit or as a complete account of each participant’s safety experience.

7. Results Posted in the Registry

• ST-246 400 mg: 75.6% (34/45) versus 93.8% (15/16) on control; risk difference -18.2 percentage points (95% CI -35.5 to -0.9), risk ratio 0.81 (0.65–0.99); unadjusted two-proportion z-test p = 0.116.
• ST-246 600 mg: 82.6% (38/46) versus 93.8% (15/16) on control; risk difference -11.1 percentage points (95% CI -27.3 to 5.0), risk ratio 0.88 (0.73–1.06); unadjusted two-proportion z-test p = 0.276.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant is counted as meeting or not meeting the stated tolerance outcome. The registry reports the number meeting the outcome in each group, and the comparison metric is a risk difference between an ST-246 group and placebo. A risk difference describes the contrast between the proportions with the outcome in two groups. A negative value in this setting corresponds to a lower observed proportion meeting the outcome in the active group than in placebo, given the comparison direction reflected in the posted estimates.

What does a confidence interval describe?

In general, a confidence interval expresses the uncertainty around an estimated effect under the method used to construct it. A narrower interval indicates greater precision, while a wider interval indicates less precision. For a risk difference, the no-difference value is zero. An interval that includes zero is compatible with no difference under that interval method; an interval lying wholly on one side of zero points to a difference in that direction under the same method. The registry record does not report the confidence level or the interval-construction method, so those details should not be assumed.

For the 400 mg comparison, the posted interval lies entirely below zero, while the unadjusted p-value is 0.116. Because the record does not explain this tension or report enough methodological detail to reconcile the summaries, the interval and p-value should be reported as distinct pieces of information. For the 600 mg comparison, the interval includes zero and the unadjusted p-value is 0.276. A p-value describes how unusual the observed data, or data more extreme, would be under a specified null model and its assumptions; it does not measure the probability that a treatment effect is real or the size of an effect.

Why can event counts affect precision?

Binary outcomes are informed by both the number of participants and how many experience the outcome. When a group is small, each participant’s outcome can have a substantial influence on the group estimate. This is particularly relevant to the placebo group, which includes 16 participants. In general, sparse counts can produce unstable estimates and wide uncertainty intervals. A risk difference is also sensitive to the underlying event proportions, so the same change in counts need not have the same interpretation across different baseline risks.

The trial has three groups, but the posted primary comparisons are each an active dose against placebo. These are separate contrasts, not a single comparison of all ST-246 participants combined. Combining groups would require a stated rationale and analysis method, neither of which is reported in the registry record. The record likewise does not report an adjusted model or covariate adjustment for the primary comparisons.

How should the p-values be read?

The posted p-values are unadjusted: 0.116 for 400 mg versus placebo and 0.276 for 600 mg versus placebo. An unadjusted p-value does not account for the possibility of testing multiple outcomes or contrasts. In general, when many hypotheses are examined, the chance of finding at least one apparently unusual result can increase unless an analysis plan addresses multiplicity. Whether and how multiplicity was handled for this trial is not reported in the registry record. The posted p-values should therefore be interpreted as the reported unadjusted comparisons, not as evidence that all possible statistical testing has been accounted for.

The registry lists eight outcome measures and seven secondary outcomes, while the analysis count is listed as zero. The secondary outcome descriptions include pharmacokinetic parameters such as Cmax, Tmax, AUCtau, and t½. Numerical results for those secondary outcomes are not reported in the registry record. The record does not state whether unreported secondary outcomes were not analyzed, were analyzed but not posted, or were handled in another way.

What does the per-protocol label establish?

The primary outcome population is described as per protocol. In general, a per-protocol analysis includes participants who meet specified study-compliance or eligibility criteria, but the specific criteria for this trial are not reported in the registry record. The record notes six withdrawals and gives their reasons, but does not explain how withdrawals affected the analysis population or how missing outcome measurements were treated. It also does not report an intention-to-treat analysis or a comparison between analysis populations. Therefore, the posted counts should be interpreted using the stated per-protocol description without assuming a particular missing-data procedure.

Randomization and double masking are design features intended in general to reduce systematic differences in treatment assignment and outcome assessment. The registry identifies the study as randomized and double-blind, but does not report the random-sequence method, allocation concealment details, or the success of masking. These features support the design description but do not, by themselves, resolve the uncertainty in the posted estimates or omissions in the analysis information.

10. Confidence Intervals and Precision

The posted comparisons have limited precision, in part because the placebo group includes 16 participants and the active groups include 45 and 46. The confidence intervals show the range of effects compatible with the data under the method used, although the registry does not report the confidence level or the interval method. In general, a wide interval signals that the estimate is uncertain; it does not mean that every value in the interval is equally plausible.

For the 400 mg comparison, the reported interval is wholly below the no-difference value, but the corresponding unadjusted p-value is 0.116. The registry record does not explain this apparent disagreement, so the two summaries should be considered separately. For the 600 mg comparison, the interval includes the no-difference value, and the unadjusted p-value is 0.276. This means the posted estimate does not pin down the direction of the difference with the same clarity as an interval entirely on one side of zero would.

Precision is not the same as importance. A point estimate can be clinically or scientifically interesting while remaining uncertain, and a small p-value would not by itself establish practical importance. Here, the main limitation is that the sample sizes, especially for placebo, leave the comparisons sensitive to the outcomes of individual participants. The registry does not provide further details that would narrow interpretation, such as a prespecified confidence level, adjusted estimates, or results from alternative analysis populations.

The primary endpoint is a count-based tolerance measure rather than a full presentation of every safety parameter. Its precision therefore concerns the reported participant-level classification, not the detailed frequency or severity of each laboratory, clinical, or electrocardiographic finding. The posted adverse-event counts are complementary safety summaries, but they do not provide precision intervals for those counts.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrative calculations based on the observed effect, not a report of the trial’s original design justification. The assumptions listed are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The planning effect is set at the stated fraction of the observed effect. The registry record does not report the trial’s own sample-size assumptions or justification.

These results are participants per arm for 80% power and participants per arm for 90% power. The 80% column gives the per-arm sample size estimated to provide an 80% chance of detecting the specified effect under the planning assumptions, if that effect and model were the true ones. The 90% column gives the corresponding per-arm sample size for a higher target chance of detection. These are planning targets, not outcomes measured in this completed trial.

The planning rows use 100%, 75%, and 50% of the observed effect. Smaller effects need more participants to detect under the same assumptions. For example, in planning for 100% of the observed effect, the 400 mg comparison lists 61 participants per arm for 80% power and 81 for 90% power; the corresponding 600 mg figures are 131 and 175. The full set of estimates varies by dose comparison and assumed effect size.

These sample-size figures are not observed power. They do not show the probability that this completed study detected an effect, nor do they revise the uncertainty in the posted results. The 400 mg and 600 mg calculations are separate planning illustrations based on their respective observed effects. Their assumptions may not match the design choices used when the trial was planned, which are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.938; treatment proportion p₁ = 0.756; average p̄ = 0.847.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5097 = 0.9991.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4932 = 0.4151.
4. n = (0.9991 + 0.4151)² / (-0.1819)² = 60.4, rounded up to 61 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.9375                          # control proportion
p1 <- 0.755555555555556                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(907803)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 61 (80% power), 81 (90% power)
 75% of observed effect: n per arm = 95 (80% power), 127 (90% power)
 50% of observed effect: n per arm = 182 (80% power), 243 (90% power)
power.prop.test: 60.4 
Simulated power at n = 61 per arm: 0.824 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry reports eight outcome measures, including seven secondary outcomes. The listed secondary outcomes concern pharmacokinetic parameters such as Cmax, Tmax, AUCtau, and t½. The analysis count is listed as zero, and numerical results for the secondary outcomes are not reported in the registry record. No multiplicity adjustment or testing hierarchy is described. Thus, the two posted primary comparisons and the listed secondary outcomes should not be assumed to form a single prespecified family of tests.

Multiplicity matters in general because examining multiple outcomes or contrasts can increase the chance of an apparently notable result arising by chance. Statistical approaches can address this issue, but the registry record does not report whether any such approach was planned or used. The posted primary-comparison p-values are unadjusted. Their interpretation should not be extended to a broader set of hypotheses without further analysis information.

The primary population is described as per protocol. The registry does not specify the criteria for inclusion in that population, whether all randomized participants were included in any other analysis, or whether an intention-to-treat analysis was performed. It reports six withdrawals and gives the stated reasons, but does not explain how withdrawals or missing measurements were handled. No imputation method, sensitivity analysis, or missing-data assumption is reported in the registry record.

These gaps matter because missing outcomes and analysis-population choices can affect both the count of participants contributing data and the estimated comparison. The posted outcome counts remain useful as the registry’s reported results, but they cannot establish how results would differ under another population definition or missing-data method. The original statistical analysis plan, prespecified multiplicity procedures, and detailed missing-data methods are not reported in the registry record.

14. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse-event figures report zero affected participants in each group: ST-246 400 mg, ST-246 600 mg, and placebo. The corresponding numbers at risk are 45, 46, and 16. The registry lists no serious adverse-event terms. The deaths field contains no reported values, so deaths are not reported in the registry record.

For other adverse events, the registry reports 11 affected participants in the 400 mg group, 8 in the 600 mg group, and 1 in placebo. These are participant counts, not event totals, and the record does not provide further detail in these figures about severity, timing, recurrence, or the specific events involved. They should be read separately from the primary tolerance counts, which were defined through changes in safety parameters under the DAIDS grading table.

A count of zero serious adverse events in the posted record does not establish that every possible safety risk is absent. The groups are limited in size, and the registry summary does not provide detailed event narratives or follow-up beyond the stated assessment period.

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

The registry record documents a randomized, double-blind comparison of two daily ST-246 doses with placebo in healthy, fed volunteers. It reports how many participants met the primary tolerance outcome in each group and provides risk-difference comparisons with unadjusted p-values and confidence intervals. The observed tolerance counts were 34 of 45 for 400 mg, 38 of 46 for 600 mg, and 15 of 16 for placebo. The posted comparisons estimate lower proportions meeting that outcome in each active group than in placebo, but their uncertainty and the apparent tension between the 400 mg interval and p-value require careful interpretation.

These results do not establish whether ST-246 is effective against orthopoxviral disease. The participants were volunteers, and the stated objectives were safety, tolerability, and pharmacokinetics. Nor do the counts provide a complete account of safety: the registry does not report the particular safety findings that determined whether each participant met the tolerance classification. The other-adverse-event counts add context, while the serious adverse-event summary reports zero affected participants in each group.

The results also do not establish that one dose is preferable. The registry states that the trial was intended to inform dose selection for expanded pivotal safety trials, but does not report a selection rule or explain how the posted findings were used. The small placebo group and the uncertainty around the comparisons limit how confidently group differences can be characterized.

Finally, the registry record does not report the original sample-size justification, detailed analysis methods, missing-data handling, or multiplicity procedures. These omissions do not erase the posted counts, but they constrain conclusions about robustness and the meaning of the statistical comparisons. The appropriate interpretation is limited to the recorded outcomes, groups, and analysis summaries.

16. Why This Trial Matters Statistically

This trial illustrates how a safety-oriented endpoint can differ from the outcomes commonly used to assess clinical benefit. Its primary measure counts participants classified as tolerating treatment according to safety-parameter changes. The result is directly connected to the stated objective of assessing tolerability and informing dose selection, but it does not by itself describe the type or severity of every safety finding.

The comparisons also show why point estimates, uncertainty intervals, and p-values should be read together. The 600 mg interval includes the no-difference value, while the 400 mg interval is entirely below it even though the unadjusted p-value is 0.116. The registry does not explain this tension. Recognizing such limitations is part of statistical interpretation: a single summary statistic should not stand in for the full account of uncertainty and methods.

The unequal group sizes, including a placebo group of 16 participants, are relevant to precision. With limited observations, a small number of participant outcomes can have a noticeable influence on a binary endpoint. The planning illustrations further show how assumed effect size and desired power change sample-size requirements, while remaining distinct from the trial’s original design justification.

Lastly, the registry’s limited information about analysis populations, missing data, multiplicity, and secondary outcome results demonstrates why a statistical reading depends on more than the reported effect estimates. Clear reporting of prespecified methods and analysis decisions helps readers distinguish planned tests from exploratory comparisons and evaluate how robust conclusions may be.

17. 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 is described as tolerance determined by safety-parameter changes according to the DAIDS grading table, but the registry does not report a more specific operational definition or threshold. The participant counts therefore cannot reveal which safety measures drove each classification. The description names broad categories of monitoring without reporting detailed results for those measures.

The registry identifies the primary population as per protocol but does not state the criteria used to define it. It reports six withdrawals and their reasons, yet does not explain how they were treated in the primary analysis or whether missing measurements were present. Details of an intention-to-treat analysis, sensitivity analyses, and missing-data procedures are not reported in the registry record.

The placebo group includes 16 participants, fewer than either active group, which limits the precision of the comparisons. The record does not report the confidence level or interval method. For the 400 mg comparison, the confidence interval lies entirely below the no-difference value while the unadjusted p-value is 0.116; the registry does not explain this apparent tension. The 600 mg interval includes the no-difference value, and its unadjusted p-value is 0.276.

The record lists seven secondary outcomes but does not report their numerical results, and it does not describe a multiplicity plan. The original sample-size justification, detailed statistical analysis plan, randomization method, allocation concealment, and masking assessment are not reported in the registry record. These limitations leave uncertainty about analysis choices and reduce the ability to assess the results beyond the posted summaries.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246 — NCT00907803.
• Registry record last updated 2026-09-11; status last verified 2010-09.
• Results first posted 2010-08-27.
• 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.

21. Record Summary

NCT00907803 is a completed Phase 2 randomized, double-blind, placebo-controlled, parallel, multicenter trial sponsored by SIGA Technologies. It evaluated ST-246 400 mg and 600 mg, each taken orally once daily for 14 days, against matching placebo in healthy, fed volunteers. The registry lists enrollment as 107 and records the start as 2009-06 and primary completion as 2010-01.

The primary outcome was the number of participants who tolerated treatment according to safety-parameter changes graded using the DAIDS adverse-event grading table. The posted counts were 34 of 45, 38 of 46, and 15 of 16 for the 400 mg, 600 mg, and placebo groups, respectively. The record also reports no serious adverse events affecting participants, while other adverse events affected 11, 8, and 1 participants in those groups.

The registry’s statistical reporting is limited: the primary comparisons have unadjusted p-values and confidence intervals, but analysis details, missing-data handling, multiplicity procedures, and numerical secondary-outcome results are not reported in the registry record.