Safety and Pharmacokinetics Study of Anthrax Immune Globulin Intravenous (AIGIV): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetics Study of Anthrax Immune Globulin Intravenous (AIGIV) (NCT00845650), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants Reporting Adverse Events (AEs).

2. Clinical Question

The clinical question is framed around safety and pharmacokinetics, not around prevention or treatment of anthrax outcomes. The primary endpoint counts participants with adverse events, while the secondary outcomes describe antibody concentrations and their behavior over time. Those pharmacokinetic measures can characterize antibody exposure, but they are not clinical outcomes such as illness or survival.

The registry lists the study as Phase 1 and Phase 2, with randomized allocation, quadruple masking, and a parallel design. It reports enrollment of 129 participants. Further information about participant eligibility, recruitment setting, and baseline clinical characteristics is not reported in the registry record, so the population represented by the results cannot be characterized more specifically from this record.

3. Trial Design

The study is titled as a randomized, double-blind, dose-escalation study of pharmacokinetics and safety. It is listed as Phase 1 and Phase 2, with quadruple masking and a parallel-group model. The registry reports a total enrollment of 129 and marks the study completed. The study began in 2009-02, and primary completion was 2010-10.

Participants were assigned to six dose groups organized into three cohorts. Cohort A included AIGIV 3.5 mg/kg anti-PA IgG and Gamunex 90 mg/kg total IgG. Cohort B included AIGIV 7.0 mg/kg anti-PA IgG and Gamunex 180 mg/kg total IgG. Cohort C included AIGIV 14.0 mg/kg anti-PA IgG and Gamunex 360 mg/kg total IgG. Each regimen is described as a single intravenous infusion. The total IgG dose and anti-PA IgG dose refer to different quantities, so the listed doses should not be interpreted as equivalent amounts of the same antibody measure.

The primary safety population was defined as all participants who received any infusion of AIGIV or Gamunex. The group sizes for the primary endpoint were 30 for AIGIV 3.5 mg/kg, 5 for Gamunex 90 mg/kg, 31 for AIGIV 7.0 mg/kg, 14 for Gamunex 180 mg/kg, 29 for AIGIV 14.0 mg/kg, and 16 for Gamunex 360 mg/kg. The PK summaries use different group sizes for the AIGIV dose groups. Why those PK sample sizes differ from the safety counts is not reported in the registry record.

The record does not report how the random sequence was generated, how allocation was concealed, or the operational details of masking. Eligibility criteria, the planned allocation ratio, and the protocol’s original sample-size justification are also not reported in the registry record. The dose-group structure and posted participant counts describe the observed trial, but do not establish why particular group sizes were selected.

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: Safety Population: all subjects who received any infusion of AIGIV or Gamunex.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Reporting Adverse Events (AEs), measured over From the time of infusion through Day 90..

The primary endpoint is the number of participants reporting adverse events from the time of infusion through Day 90. An adverse event is defined broadly as an untoward medical occurrence reported to or observed by the principal investigator, including events identified through other safety assessments such as vital signs, clinical laboratory testing, and electrocardiograms. The outcome is a count of participants with at least one reported event, rather than a count of every event episode.

This kind of endpoint is used to describe the observed safety experience during a defined follow-up period. It allows the reader to see how many participants in each group experienced an event under the registry’s definition. The group sizes matter when interpreting those counts: the same count can represent a different proportion of participants in groups of different sizes. The posted comparisons express differences in event risk as risk differences and include uncertainty intervals where available.

The endpoint does not, by itself, show that an infusion caused an event. The registry definition includes events reported or observed during follow-up, and the posted count does not distinguish events by severity, expectedness, or causal attribution. Serious adverse events are separately summarized in the safety information. The primary endpoint is therefore a broad descriptive safety measure, not a complete account of the nature or cause of every medical occurrence.

The record names the safety population as participants who received any infusion. It does not report a more detailed primary-endpoint analysis plan, including rules for handling participants with incomplete follow-up or events that began before infusion. Those details are important when interpreting how the endpoint was assembled but are not reported in the registry record.

7. Results Posted in the Registry

• AIGIV 7.0 mg/kg (Cohort B): 93.5% (29/31) versus 93.3% (28/30) on control; risk difference 0.2 percentage points (95% CI -12.2 to 12.6), risk ratio 1.00 (0.88–1.14); unadjusted two-proportion z-test p = 0.973.
• Gamunex 180 mg/kg (Cohort B): 78.6% (11/14) versus 93.3% (28/30) on control; risk difference -14.8 percentage points (95% CI -38.0 to 8.5), risk ratio 0.84 (0.63–1.12); unadjusted two-proportion z-test p = 0.151.
• AIGIV 14.0 mg/kg (Cohort C): 100.0% (29/29) versus 93.3% (28/30) on control; risk difference 6.7 percentage points (95% CI -2.3 to 15.6), risk ratio 1.07 (0.97–1.18); unadjusted two-proportion z-test p = 0.157.
• Gamunex 360 mg/kg (Cohort C): 93.8% (15/16) versus 93.3% (28/30) on control; risk difference 0.4 percentage points (95% CI -14.4 to 15.3), risk ratio 1.00 (0.86–1.18); unadjusted two-proportion z-test p = 0.957.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • AIGIV 7.0 mg/kg (Cohort B): mean 2.21 versus 1.07 on control; difference 1.14 (95% CI 0.94 to 1.34), standardized effect d = 2.94; z-test p = <0.001.
  • AIGIV 14.0 mg/kg (Cohort C): mean 4.31 versus 1.07 on control; difference 3.24 (95% CI 2.86 to 3.62), standardized effect d = 4.48; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for AIGIV 7.0 mg/kg (Cohort B) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for AIGIV 14.0 mg/kg (Cohort C) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Time of Cmax

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • AIGIV 7.0 mg/kg (Cohort B): mean 7.81 versus 4.49 on control; difference 3.32 (95% CI -6.65 to 13.29), standardized effect d = 0.17; z-test p = 0.514.
  • AIGIV 14.0 mg/kg (Cohort C): mean 7.35 versus 4.49 on control; difference 2.86 (95% CI -6.95 to 12.67), standardized effect d = 0.15; z-test p = 0.568.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between AIGIV 7.0 mg/kg (Cohort B) and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between AIGIV 14.0 mg/kg (Cohort C) and the control. The interval gives the range of effects that remain compatible with the data.

Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t])

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • AIGIV 7.0 mg/kg (Cohort B): mean 636.31 versus 323.03 on control; difference 313.28 (95% CI 187.77 to 438.79), standardized effect d = 1.34; z-test p = <0.001.
  • AIGIV 14.0 mg/kg (Cohort C): mean 1,277 versus 323.03 on control; difference 954.27 (95% CI 817.52 to 1,091), standardized effect d = 3.72; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for AIGIV 7.0 mg/kg (Cohort B) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for AIGIV 14.0 mg/kg (Cohort C) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary results focus on toxin-neutralizing antibody measurements after AIGIV. Across the posted dose groups, the general pattern is that higher AIGIV doses are associated with higher reported maximum concentrations and greater area under the concentration-time curve. The timing of the maximum concentration does not display the same clear dose-related pattern. These measures describe different aspects of antibody exposure: a peak level, the timing of that peak, and accumulated exposure over follow-up.

The registry lists additional pharmacokinetic outcomes, including area under the curve to infinity, elimination rate, elimination half-life, and mean residence time. Detailed numeric results for those outcomes are not reported in the registry record. The posted numeric summaries focus on selected outcomes and compare AIGIV dose groups; equivalent numeric PK summaries for the Gamunex arms are not reported in the registry record. The secondary results therefore do not provide a complete pharmacokinetic comparison of all six regimens.

The PK findings are distinct from the primary safety endpoint. A pattern in antibody concentration does not establish that participants experienced fewer adverse events, nor does it establish clinical protection against anthrax. The primary outcome counts participants with adverse events, while the secondary outcomes characterize measured antibody levels. They answer different questions and should not be collapsed into a single conclusion.

Unadjusted secondary comparisons carry less inferential weight when many outcomes and comparisons are considered. The registry record does not report a multiplicity plan, a prespecified hierarchy among PK outcomes, or which secondary comparisons were confirmatory. Without that information, the posted p-values are best treated as exploratory descriptions of the measured data rather than as definitive evidence across a family of tests. In addition, the PK sample sizes are smaller than some safety group sizes, and the record does not explain why measurements are unavailable for some participants.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Maximum Plasma Titer/Concentration of TNA (Toxin Neutralizing Antibody) (Cmax)
• Time of Cmax
• Area Under the Curve to the Last Time With a Measurable TNA Titer (AUC[0-t])
• Area Under the Curve to Infinity (AUC[0-inf])
• Elimination Rate Constant
• Elimination Half-life (t½)
• Mean Residence Time (MRT)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is binary at the participant level: each participant either contributed to the count of participants reporting an adverse event or did not. A risk is the proportion of a group with the event. A risk difference compares two such proportions by subtracting the reference-group risk from the other group’s risk. A value near zero means the observed proportions are close; a positive or negative value indicates which group had the higher observed risk, according to the comparison’s direction. Risk differences are expressed on the probability scale, rather than as a relative change.

What does an interval estimate convey?

An interval estimate gives a range of values compatible with the observed data under the method used. A narrow interval indicates greater precision; a wide interval indicates greater uncertainty about the size and direction of the difference. If an interval includes zero for a risk difference, the data are compatible with no difference as well as with some difference in either direction. The registry record does not state the confidence level used for the posted intervals, so no particular confidence percentage should be attached to them.

The registry also posts relative measures for some comparisons: the risk ratio and, in some cases, the odds ratio. A risk ratio compares the event risks directly, while an odds ratio compares the event odds. These relative measures can be less intuitive than an absolute risk difference, especially when events are common. They also have their own intervals and should not be read as substitutes for the event counts. Because the primary endpoint is frequent in these small groups, the observed counts and absolute comparisons remain useful context for interpreting any relative estimate.

How should the p-values be read?

A p-value describes how unusual data at least as incompatible with a specified null model would be if that model and the test assumptions held. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of a difference. The posted p-values are explicitly unadjusted. The registry record does not describe the testing procedure, any prespecified hierarchy, or adjustment for testing multiple comparisons. A small unadjusted p-value on a secondary measure should therefore be treated cautiously when many outcomes or comparisons are considered.

The record includes both binary safety outcomes and continuous PK outcomes. For continuous outcomes, the posted summaries include a mean and standard deviation. The mean describes the group’s average measurement, while the standard deviation describes the spread of individual measurements around that average. The mean difference compares two group averages. Its interval expresses uncertainty about that difference, and its p-value concerns a null hypothesis of no mean difference under the test used. The PK sample sizes vary by outcome group; the registry does not explain the reasons for that variation.

Why can small groups produce uncertain safety estimates?

When group sizes are small, each participant’s event status has substantial influence on the observed group proportion. This makes estimates sensitive to individual outcomes and generally limits precision. Unequal group sizes can add to that limitation because the smaller group often contributes less information to a comparison. The Gamunex groups are smaller than the AIGIV groups in the posted safety summaries, with particularly few participants in Cohort A. The wide intervals in some comparisons are consistent with considerable uncertainty about the size of any difference.

Over-dispersion is a general concern when observed variability is greater than assumed by a statistical model. In that situation, a model that understates variability may produce intervals that are too narrow and tests that appear more conclusive than warranted. The registry record does not report whether an over-dispersion assessment was conducted for these endpoints or whether any adjustment was used. For the continuous PK outcomes, the group standard deviations and sample sizes give some descriptive information about spread, but they do not establish that a particular distributional assumption is appropriate.

What can the planning calculations tell us?

The posted sample-size calculations are illustrations based on observed effects and stated planning assumptions, not evidence that the trial was originally designed around those assumptions. They vary the effect to detect by considering the observed effect and smaller fractions of it. Smaller effects require more participants to distinguish them from random variation at the same planning criteria. Calculations based on an observed effect can be especially unstable when the study groups are small, because the observed effect itself may be imprecise.

The record does not report the trial’s original sample-size justification, interim analyses, or complete statistical analysis plan. It also does not describe the approach to missing observations, protocol deviations, or sensitivity analyses. Those omissions limit what can be concluded about whether the posted comparisons reflect prespecified analyses or how robust the results are to alternative analytic choices. Statistical summaries can describe the available results, but they cannot supply the missing protocol decisions.

11. Confidence Intervals and Precision

Precision is limited for the primary safety comparisons. The risk-difference interval for AIGIV 7.0 mg/kg versus the AIGIV 3.5 mg/kg reference runs from -0.122 to 0.126. For Gamunex 180 mg/kg versus the reference, it runs from -0.380 to 0.085. For AIGIV 14.0 mg/kg, it runs from -0.023 to 0.156, and for Gamunex 360 mg/kg it runs from -0.144 to 0.153. Each interval includes zero and also permits differences in either direction.

The interval for Gamunex 180 mg/kg is particularly broad, consistent with the small group size of 14. The AIGIV 14.0 mg/kg estimate is based on 29 participants, while the reference group includes 30. Even with groups of that size, the interval leaves uncertainty around the magnitude of the difference. The Gamunex 90 mg/kg group has 5 participants, and no primary risk-difference interval or comparison estimate for that group is posted against the reference.

The registry record does not identify the confidence level for the intervals. They can be interpreted as interval estimates expressing uncertainty, but the record does not support assigning them a stated confidence percentage. The unadjusted p-values likewise do not remedy the uncertainty in the estimated effects: a p-value is not a measure of precision and does not show which differences remain plausible.

For the continuous PK outcomes, interval widths differ across comparisons. Some posted intervals are relatively separated from zero, while others cover zero and span both negative and positive mean differences. The observed mean differences and intervals are specific to these study samples; they should not be treated as precise estimates for a broader population without considering the unreported eligibility details, analysis choices, and missing-data handling.

12. 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 sample-size figures are planning illustrations, not the trial’s original design targets. For these binary safety comparisons and continuous PK comparisons, the stated figures are participants per arm. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The target effect is set to the stated fraction of the observed effect. There are no time-to-event planning results in these calculations, so the figures are not total event counts.

The 80% power column means the number of participants per arm estimated to give an 80% chance of detecting the specified effect if the planning assumptions and effect model hold. The 90% power column applies the same idea at a higher chance of detection, and consequently generally calls for a larger planned sample. These are prospective planning quantities: they describe hypothetical future group sizes under stated assumptions, not the probability that the completed study detected an effect.

For example, the planning illustration for Gamunex 180 mg/kg versus the AIGIV 3.5 mg/kg reference gives 86 participants per arm for 80% power and 115 for 90% power when planning around 100% of the observed effect. At 50% of that observed effect, the corresponding figures are 267 and 357 participants per arm. A smaller effect is harder to distinguish from random variation, so smaller effects require more participants under the same assumptions.

Some PK calculations yield very small planning figures when based on large observed effects. Such estimates should not be read as proof that only a very small future study would be adequate: they inherit uncertainty and possible exaggeration in effects observed in small groups. The registry’s original sample-size assumptions and justification are not reported in the registry record. These planning figures are not observed power.

13. 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 = 0.933; treatment proportion p₁ = 0.935; average p̄ = 0.934.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3501 = 0.6862.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3501 = 0.2947.
4. n = (0.6862 + 0.2947)² / (0.0022)² = 208,029.5, rounded up to 208,030 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 <- 0.933333333333333                          # control proportion
p1 <- 0.935483870967742                          # 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(845650)
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 = 208,030 (80% power), 278,492 (90% power)
 75% of observed effect: n per arm = 371,240 (80% power), 496,985 (90% power)
 50% of observed effect: n per arm = 838,460 (80% power), 1,122,459 (90% power)
power.prop.test: 208029.5 
Simulated power at n = 208,030 per arm: 0.804 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the investigators adjusted for testing multiple outcomes or comparisons. This matters because the study evaluated a primary safety endpoint alongside multiple pharmacokinetic outcomes and dose groups. When many tests are performed, the chance of at least one apparently unusual result can increase even when there is no underlying effect. A multiplicity plan can control that concern, but no such plan is reported in the registry record.

The posted comparison p-values are unadjusted. They should therefore be interpreted as individual, exploratory results rather than as a family of tests with a stated overall error rate. The record does not describe a primary-versus-secondary testing hierarchy, a gatekeeping procedure, or which outcomes were intended to support confirmatory claims. The analysis plan and protocol’s prespecified contrasts are not reported in the registry record.

Missing-data handling is also not reported. The safety endpoint is defined for participants who received an infusion, but the record does not describe how incomplete follow-up through Day 90 was handled, whether all participants were observed for the full timeframe, or whether any imputation or sensitivity analysis was used. The PK summaries have smaller sample sizes than the safety groups. Reasons for those differences, such as unavailable measurements or other analysis requirements, are not reported in the registry record and should not be assumed.

The safety population is explicitly described as all participants who received any infusion. A separate intention-to-treat population or per-protocol population is not described in the posted information. The registry record does not report whether exclusions occurred after randomization, how protocol deviations were treated, or whether analyses were performed according to assigned group regardless of treatment received.

These omissions do not invalidate the descriptive counts or means, but they limit assessment of how the analysis was planned and how sensitive results may be to missing observations or alternative populations. The record also does not report interim analyses, stopping rules, or a detailed statistical analysis plan. Without these details, the comparisons should be understood as the results posted in the registry rather than as a fully documented confirmatory analysis.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: sepsis syndrome (7.1%), gun shot wound (7.1%), abdominal pain (3.3%), intra-uterine death (3.2%).

Serious adverse events were reported for 1 of 30 participants receiving AIGIV 3.5 mg/kg, 0 of 5 receiving Gamunex 90 mg/kg, 1 of 31 receiving AIGIV 7.0 mg/kg, 1 of 14 receiving Gamunex 180 mg/kg, 0 of 29 receiving AIGIV 14.0 mg/kg, and 0 of 16 receiving Gamunex 360 mg/kg. The registry reports zero deaths in each group. These are observed counts, and the small group sizes mean that each count represents a limited amount of information about uncommon serious events.

The registry also lists serious-event terms with percentages: Sepsis syndrome, 7.1%; Gun shot wound, 7.1%; Abdominal pain, 3.3%; and Intra-uterine death, 3.2%. The record does not make clear how these terms map to treatment groups in the posted term list, so they should not be assigned to a particular regimen based on this information alone.

Serious-event counts and the broader primary adverse-event counts are different safety summaries. The registry’s broad adverse-event definition includes untoward medical occurrences identified through observation or safety assessments; it does not establish causality. The serious-event counts likewise describe events observed during the study and do not, by themselves, identify whether an infusion caused them.

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

The posted results describe adverse-event counts and selected antibody pharmacokinetic measurements in a randomized, masked, dose-escalation study. They show that adverse events were common across the safety groups during follow-up and that serious adverse events were recorded in some groups, with no deaths reported. The primary comparisons against AIGIV 3.5 mg/kg have intervals that include zero and are imprecise, so the data do not establish a clear difference in the risk of participants reporting adverse events across those comparisons.

The results also show a pattern of higher measured peak antibody concentration and area under the curve at higher AIGIV doses. Those measurements are pharmacokinetic outcomes. They do not show whether AIGIV or Gamunex prevents anthrax, treats anthrax, improves survival, or changes any other clinical outcome. No clinical efficacy outcome is reported in the registry record.

The absence of a statistically clear difference in a comparison is not evidence that the regimens are equivalent. Equivalence or noninferiority requires a prespecified margin and an analysis designed to assess that question; such a margin and analysis are not reported in the registry record. Wide intervals and small group sizes leave room for effects in either direction. Similarly, an unadjusted small p-value for a PK outcome does not establish clinical importance or overcome uncertainty about multiple testing.

The results are specific to the participants studied, the single-infusion regimens, and the follow-up described in the record. Eligibility details, the original sample-size justification, handling of missing data, and a full statistical analysis plan are not reported. These limits make it difficult to assess generalizability and analytic robustness from the registry record alone.

Accordingly, the posted data are best read as descriptive evidence about safety observations and measured antibody exposure in this study. They should not be interpreted as medical advice or as proof that any regimen works or does not work for anthrax. The record does not supply the clinical outcome evidence needed to answer a treatment-effect question.

17. Why This Trial Matters Statistically

This trial raises several statistical issues that recur in early-phase clinical research. A dose-escalation study can produce useful information about observed safety and biological measurements, but the group sizes may be limited and the primary focus may not be a definitive comparison of clinical outcomes. The small groups in this record make event counts easy to interpret descriptively, while leaving substantial uncertainty about differences between regimens.

The study also illustrates why absolute and relative comparisons should be read alongside raw counts. A risk difference communicates an absolute contrast in event risk, while a risk ratio or odds ratio expresses a relative contrast. When events are common and denominators differ, these measures can tell different-looking stories unless the reader keeps the underlying counts and group sizes in view. Here, the comparisons against the AIGIV 3.5 mg/kg reference have wide intervals, and the reference is not compared statistically with every other regimen in the posted primary results.

Pharmacokinetic outcomes add another layer: they characterize exposure, not clinical benefit. A dose-related pattern in measured antibody levels can be scientifically informative, but it does not answer whether participants experience a clinical outcome. Keeping safety, PK, and efficacy questions separate is central to sound interpretation.

Finally, the record highlights the importance of prespecified analysis details. Multiplicity handling, missing-data methods, analysis populations, and sample-size justification affect how strongly a result can be interpreted. When those details are not reported, readers can describe the posted estimates and their precision, but cannot determine whether the results follow a planned confirmatory strategy or how robust they are to alternative choices.

18. 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 group sizes are small and uneven, particularly in the Gamunex groups. The 90 mg/kg group includes 5 participants, and the 180 mg/kg group includes 14. Consequently, the safety counts provide limited information about uncommon events and the risk-difference estimates are uncertain. The registry’s primary comparisons use AIGIV 3.5 mg/kg as the reference; it does not post a direct estimate for Gamunex 90 mg/kg against that group or direct same-cohort AIGIV-versus-Gamunex safety contrasts.

The PK summaries cover fewer participants than the safety summaries. The record does not report why measurements are missing from those analyses, how missing measurements were handled, or whether the analyzed participants differ from those without reported PK values. Numeric results for several listed pharmacokinetic outcomes are not reported in the registry record. The posted numeric PK summaries focus on AIGIV and do not provide a complete comparison of pharmacokinetics across all six arms.

The primary endpoint is a broad count of participants reporting adverse events through Day 90. The posted count does not convey event duration, recurrence, severity for non-serious events, or attribution to the infusion. Although serious adverse events are separately counted, the record’s list of serious-event terms does not identify their treatment-group assignments. No deaths were reported in any group, but small samples limit conclusions about rare outcomes.

The registry record does not report the eligibility criteria, baseline characteristics, randomization procedure, full statistical analysis plan, multiplicity handling, missing-data methods, or original sample-size justification. Follow-up beyond Day 90 and clinical efficacy outcomes are not reported. These limitations restrict conclusions about generalizability, precision, and treatment effects beyond the safety and PK observations posted for this study.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetics Study of Anthrax Immune Globulin Intravenous (AIGIV) — NCT00845650.
• Registry record last updated 2024-03-18; status last verified 2024-03.
• Results first posted 2018-06-13.
• 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.

22. Record Summary

NCT00845650 is a completed randomized, double-blind, dose-escalation study of AIGIV and Gamunex, listed in Phase 1 and Phase 2. The parallel study enrolled 129 participants and evaluated single intravenous infusions across three AIGIV doses and three corresponding Gamunex doses. The primary endpoint counted participants reporting adverse events from infusion through Day 90.

Most participants in each safety group had at least one reported adverse event. Serious adverse events were reported in three of the six groups, and the registry reports zero deaths in all groups. The primary risk-difference intervals against AIGIV 3.5 mg/kg include zero and are broad. Selected AIGIV pharmacokinetic summaries show higher peak concentration and area-under-the-curve values in the higher-dose cohorts, while the registry does not report numeric results for several listed PK outcomes.

The record does not report the original sample-size justification, detailed analysis plan, multiplicity strategy, or missing-data methods. The posted findings describe safety observations and antibody pharmacokinetics; clinical efficacy results are not reported in the registry record.