Study of AERAS-402 in Healthy Infants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of AERAS-402 in Healthy Infants (NCT01198366), a randomized phase 1, phase 2 study. The primary outcome is Adverse Events Collected Per Subject.

2. Clinical Question

The registry describes a study of AERAS-402 in infants who had already received BCG vaccination. Eligible participants were at least 16 weeks of age, HIV-uninfected, and without evidence of tuberculosis. The study’s stated aim was to evaluate whether AERAS-402 would increase protection against tuberculosis, while its posted primary outcome measures adverse events.

The posted primary outcome is not a measure of tuberculosis protection. It records the percentage of subjects with an adverse event, with adverse events recorded for 28 days after vaccination and serious adverse events recorded over the study period. The registry lists immune-response measures and conversion from a negative to a positive QuantiFERON test as secondary outcomes, but their results are not reported in the registry record. Consequently, the posted results address safety-event reporting and do not provide a result for the study’s stated protection aim.

3. Trial Design

This was a randomized, quadruple-masked, parallel-group study described in the official title as Phase II, double-blind, placebo-controlled, and multicenter. The registry categorizes the study as both Phase I and Phase II. It reports an enrollment of 487 and a completed status. The recorded start was 2010-09, and primary completion was 2014-01.

Participants were assigned to dose-finding groups or an expanded safety phase. In dose finding, the placebo group and the groups receiving AERAS-402 at 1.5 x 10^10 vp, 3.0 x 10^10 vp, or 1.0 x 10^11 vp were each scheduled for two vaccinations on study days 0 and 28. The expanded safety phase compared three doses of AERAS-402 at 1.0 x 10^11 vp with three doses of placebo, administered on days 0, 28, and 280. These are the arm schedules described in the registry.

The posted primary outcome is the percentage of subjects with an adverse event among those who received at least one vaccination. The outcome timeframe is up to 24 months post vaccination. Its description distinguishes adverse events recorded for 28 days after vaccination from serious adverse events recorded for the entire study period. The registry lists five outcome measures, including the primary safety outcome and secondary immune-response measures.

The reported risk-difference comparisons use the expanded safety placebo group as the control for each AERAS-402 group. This gives the comparisons a common listed placebo reference, even though the dose-finding placebo group had a different schedule. The registry record does not report the rationale for this comparison structure, the original sample-size justification, or further details of the allocation procedure.

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: Subjects who received at least one vaccination.

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 Adverse Events Collected Per Subject, measured over Up to 24 months post vaccination.

The primary outcome is titled “Adverse Events Collected Per Subject” and is expressed as the percentage of subjects with an adverse event. The population for this outcome comprises subjects who received at least one vaccination. The registry states that adverse events are recorded for 28 days post vaccination, while serious adverse events are recorded for the entire study period; the outcome timeframe is listed as up to 24 months post vaccination.

This kind of endpoint is used to describe the frequency of reported safety events during a study. It can show how often participants in each group had an event under the registry’s reporting definition and follow-up period. It does not, by itself, establish that an event was caused by a vaccination. The posted outcome is a participant-level percentage, not a count of all event episodes: a participant can have an event, but the reported measure concerns whether a subject had an adverse event.

The registry reports percentages of 94.2% and 96.1% for Dose Finding Groups 1 and 2, and 100.0% for Dose Finding Groups 3 and 4 and the expanded safety AERAS-402 group. The expanded safety placebo group is reported as 98.6%. No arm-level confidence intervals are listed alongside these percentages. The outcome therefore describes the observed proportion in each group, while the precision of differences between groups is addressed separately by the posted comparisons.

The endpoint is a safety measure, not a direct measure of tuberculosis prevention or immune protection. The listed immune-response outcomes are secondary, and their results are not reported in the registry record.

7. Results Posted in the Registry

• Dose Finding - Group 1: 94.2% (49/52) versus 98.6% (139/141) on control; risk difference -4.4 percentage points (95% CI -11.0 to 2.3), risk ratio 0.96 (0.89–1.03); unadjusted two-proportion z-test p = 0.091.
• Dose Finding - Group 2: 96.1% (49/51) versus 98.6% (139/141) on control; risk difference -2.5 percentage points (95% CI -8.2 to 3.2), risk ratio 0.97 (0.92–1.03); unadjusted two-proportion z-test p = 0.283.
• Dose Finding - Group 3: 100.0% (51/51) versus 98.6% (139/141) on control; risk difference 1.4 percentage points (95% CI -0.5 to 3.4), risk ratio 1.01 (0.99–1.03); unadjusted two-proportion z-test p = 0.393.
• Dose Finding - Group 4: 100.0% (52/52) versus 98.6% (139/141) on control; risk difference 1.4 percentage points (95% CI -0.5 to 3.4), risk ratio 1.01 (0.99–1.03); unadjusted two-proportion z-test p = 0.388.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a subject is counted as having experienced an adverse event or not, and the group result is the percentage of participants with an event. In general, binary outcomes are often summarized as proportions and compared using measures such as a risk difference or a risk ratio. The posted comparisons use risk differences; the registry also lists risk ratios for some comparisons.

What does a risk difference describe?

A risk difference subtracts one group’s event proportion from the other group’s event proportion, with direction determined by the comparison. A value below zero means the proportion in the named AERAS-402 group is lower than in the placebo reference group; a value above zero means it is higher. The estimates are reported on the proportion scale. For example, the listed estimate for Dose Finding Group 1 is -0.043. That estimate is a summary of the difference between groups, not a count of participants and not an estimate of causation.

The comparisons name each AERAS-402 group and use Expanded Safety Phase Group 5 Placebo as the reference. For these estimates, the registry lists the event counts and group sizes used in each comparison. The listed comparison group sizes need not be the same as the enrollment for the entire trial: they refer to the groups contributing to that particular comparison. The primary outcome population is subjects who received at least one vaccination.

How should the confidence interval be read?

In general, a confidence interval expresses uncertainty around an estimated effect. Its endpoints indicate a range of effect values compatible with the data under the method used to construct the interval. A wider interval indicates less precision than a narrower interval, all else being equal. An interval that includes zero for a risk difference is compatible with no group difference, as well as with nonzero differences within its bounds. The posted risk-difference intervals include zero for every listed comparison.

The confidence intervals and p-values answer related but different questions. A p-value summarizes how surprising the data would be under a specified null model; it is not the probability that the null hypothesis is true, nor a measure of the size of an effect. The listed p-values are explicitly unadjusted. The registry record does not report whether or how multiplicity was accounted for in the trial’s own analysis.

Why do group sizes and event frequencies matter?

Precision depends in part on how much information the data contain. In general, estimates based on more participants tend to be more precise when other features are comparable. The event percentages in this trial are high across groups, so comparisons are made between proportions near the upper bound of the percentage scale. In general, when outcomes are very common, the possible range for an increase is constrained, while a decrease may remain possible; interpretation depends on the observed counts and interval, not the percentage alone.

For binary data, the amount of information is influenced by the event and non-event counts in each group. A percentage without an interval gives a point summary but does not show its uncertainty. The registry does not list confidence intervals for the arm-level percentages. The comparative intervals provide uncertainty estimates for the risk differences, but the record does not state all details of the method used to calculate them.

What is the role of the secondary outcomes?

The registry lists four secondary outcome descriptions: cytokine expression measured by intracellular cytokine staining, an interferon-gamma ELISpot response, antigen-specific antibody response measured as mean optical density, and conversion from a negative to a positive QuantiFERON test. These outcomes address immune responses or test status rather than the primary adverse-event percentage. Their results are not reported in the registry record. No numerical interpretation of those outcomes is therefore possible from the posted results.

In general, immune-response measures may have different data structures from binary adverse-event outcomes. A percentage of cells, a spot-forming-unit measure, a mean optical density, and a conversion percentage are not interchangeable measures. The registry record does not report further details of the planned statistical methods for these outcomes, including how repeated measurements, assay distributions, or missing measurements were to be handled.

What analysis details are not available?

The registry reports no analyses count and does not provide a detailed statistical analysis plan in the record. The original sample-size justification, planned analysis populations beyond the primary outcome population, missing-data procedures, and any interim-analysis plan are not reported in the registry record. The listed comparisons carry unadjusted p-values, but the record does not describe a multiplicity strategy. These gaps limit assessment of whether the posted comparisons match a prespecified analysis or how the study handled all outcomes and participants.

In general, statistical methods are most informative when read alongside the population definition, timing, outcome definition, and analysis plan. Here, the primary outcome is defined for vaccinated subjects, the posted timeframe is up to 24 months post vaccination, and the registry distinguishes the shorter adverse-event recording period from the full-study serious-adverse-event period. The listed estimates should be interpreted within those stated definitions and the limitations of the analysis details reported in the registry.

10. Confidence Intervals and Precision

The arm-level percentages are point estimates. The registry does not report confidence intervals alongside those percentages, so their uncertainty cannot be judged directly from the arm summaries alone. The comparative risk differences do include confidence intervals, which show the range of values compatible with each estimated contrast under the interval method used.

For Dose Finding Group 1 versus the expanded safety placebo group, the risk difference is -0.043, with an interval from -0.110 to 0.023. For Dose Finding Group 2, it is -0.025, with an interval from -0.082 to 0.032. Dose Finding Group 3 has an estimate of 0.014 and an interval from -0.005 to 0.034; the same estimate and interval are listed for Dose Finding Group 4 and the expanded safety AERAS-402 group. All of these intervals include zero, so they do not rule out no difference in the risk of a recorded adverse event.

In general, an interval is not a guarantee that the true effect lies within its endpoints. It is a measure of statistical uncertainty under the assumptions and method used. The registry record does not report the interval-construction method. The intervals should be considered with the group sizes and event counts, which vary across comparisons, and with the fact that the endpoint percentages are high in all groups. A point estimate alone can look more definite than the data warrant; the interval communicates that uncertainty.

The unadjusted p-values are 0.091, 0.283, 0.393, 0.388, and 0.157 for the listed comparisons in order from Dose Finding Group 1 through the expanded safety AERAS-402 group. These values are not measures of effect size or precision, and they do not adjust for multiple comparisons. The registry record does not report an adjustment strategy.

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 sample-size figures are planning illustrations based on the observed effect, not the trial’s original design justification. The assumptions listed for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The listed quantities are participants per arm, not total participants and not total events.

For the comparison involving Dose Finding Group 1, the rows use 100%, 75%, and 50% of the observed effect. At 100% of the observed effect, the illustration gives 287 participants per arm for 80% power and 383 participants per arm for 90% power. At 75%, it gives 435 and 582 participants per arm, respectively. At 50%, it gives 810 and 1,083 participants per arm.

For Dose Finding Group 2, the corresponding figures are 650 and 870 participants per arm at 100% of the observed effect; 1,024 and 1,371 at 75%; and 2,006 and 2,685 at 50%. The sample-size section gives these illustrations for those comparisons; it does not report corresponding figures for the other listed comparisons.

In plain language, the 80% power column indicates the illustrated per-arm sample size for an analysis with an 80% chance of detecting the specified effect under the stated assumptions, if that effect is present. The 90% power column uses a higher target chance and therefore has larger figures in these rows. Smaller effects require more participants in the illustrations because they are harder to distinguish from random variation. These are planning calculations, not observed power.

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 = 0.986; treatment proportion p₁ = 0.942; average p̄ = 0.964.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2632 = 0.5159.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2614 = 0.2200.
4. n = (0.5159 + 0.2200)² / (-0.0435)² = 286.1, rounded up to 287 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 <- 0.985815602836879                          # control proportion
p1 <- 0.942307692307692                          # 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(1198366)
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 = 287 (80% power), 383 (90% power)
 75% of observed effect: n per arm = 435 (80% power), 582 (90% power)
 50% of observed effect: n per arm = 810 (80% power), 1,083 (90% power)
power.prop.test: 286.1 
Simulated power at n = 287 per arm: 0.835 (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 lists five outcome measures: the adverse-event primary outcome and four secondary outcomes covering cytokine expression, an interferon-gamma ELISpot response, antigen-specific antibody response, and QuantiFERON conversion. It also lists five AERAS-402-versus-placebo comparisons for the primary outcome. Testing multiple outcomes or comparisons can increase the chance of obtaining at least one apparently unusual result by chance. In general, a multiplicity plan specifies how such testing is handled, for example through adjusted thresholds or a prespecified testing order.

The reported p-values for the risk-difference comparisons are unadjusted. A multiplicity adjustment or a prespecified hierarchy is not reported in the registry record. The record also does not report whether the primary outcome was analyzed as the sole confirmatory comparison, whether the comparisons were exploratory, or how secondary outcomes were incorporated into any overall interpretation. The posted results should therefore be read as individual unadjusted comparisons rather than as evidence that a family-wise testing procedure was used.

The primary endpoint population is described as subjects who received at least one vaccination. The registry record does not report further analysis-population definitions, such as how randomized participants who did not receive vaccination would be treated or whether analyses followed assignment regardless of vaccination. Missing-data procedures, the amount and pattern of missing outcome data, and any sensitivity analyses for missing data are also not reported in the registry record.

Those omissions matter because an analysis can depend on which participants contribute data and how unavailable measurements are handled. In general, excluding participants with missing data can affect estimates if missingness is related to outcome or group, while assumptions used to handle missingness also introduce uncertainty. No particular missing-data mechanism or procedure can be inferred from the registry record.

The registry lists four secondary outcomes but does not report their results. It also does not describe interim analyses, stopping rules, or the statistical analysis plan. These items are not reported in the registry record, so their role in the design and analysis cannot be assessed from the posted information.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: malaria (35.3%), pneumonia (19.2%), gastroenteritis (13.7%), lower respiratory tract infection (3.9%), bronchiolitis (3.8%).

The serious adverse-event summaries report the number of participants at risk and the number affected in each group. The dose-finding groups list 20 of 52, 25 of 51, 23 of 51, and 18 of 52 affected, respectively. The expanded safety AERAS-402 group lists 40 of 140 affected, while the expanded safety placebo group lists 38 of 141 affected. These counts describe participants with serious adverse events; they are not counts of every serious event episode.

The registry also lists other adverse events separately. The numbers affected are 48 of 52, 47 of 51, 49 of 51, and 52 of 52 across Dose Finding Groups 1 through 4; 136 of 140 in the expanded safety AERAS-402 group; and 139 of 141 in the expanded safety placebo group. These summaries are distinct from the serious-event counts and should not be conflated with the primary endpoint percentages.

The listed serious-event terms include Malaria at 35.3%, Pneumonia at 19.2%, Gastroenteritis at 13.7%, Lower respiratory tract infection at 3.9%, Bronchiolitis at 3.8%, and Measles at 3.8%. The registry record does not provide further context for interpreting the denominators of these term percentages in the posted summary. Death counts are not reported in the registry record. The presence of an event in these summaries does not establish that it was caused by vaccination.

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

The posted results describe adverse-event reporting in six study groups: four dose-finding groups and two expanded safety groups. Adverse events were reported for a high percentage of subjects in every group, ranging from 94.2% to 100.0%. The expanded safety placebo group is reported at 98.6%, while the expanded safety AERAS-402 group is reported at 100.0%. These are observations in the study groups under the registry’s endpoint definition and follow-up description.

The comparative estimates are relatively close to zero, and every listed risk-difference confidence interval includes zero. This means the posted estimates do not precisely distinguish a difference from no difference for these comparisons. The intervals also allow values on either side of zero, so the point estimates should not be treated as definitive evidence of a group difference or equivalence. The registry record does not report an equivalence or non-inferiority framework.

The outcome is a safety measure. It does not measure whether tuberculosis was prevented, and the record’s stated aim of evaluating protection cannot be answered from the primary outcome results. Although four immune-related secondary outcomes are listed, their results are not reported in the registry record. Accordingly, the posted information does not show whether AERAS-402 changed those immune measures or QuantiFERON conversion.

The reported adverse-event percentages also do not establish causation. The study’s randomized, masked design is relevant context, but interpretation still depends on outcome definitions, follow-up, participant populations, event attribution, and analysis methods. The registry record does not report all of those details. Serious adverse-event counts and the listed event terms provide additional safety descriptions, but they do not on their own determine whether an event was related to vaccination.

Overall, the registry supports a cautious description of the recorded safety outcomes and the unadjusted comparisons against the expanded safety placebo group. It does not support a conclusion about tuberculosis protection from these posted results, nor does it provide a complete account of the statistical plan or all secondary-outcome findings.

16. Why This Trial Matters Statistically

This trial illustrates why the endpoint and the study’s stated scientific aim need to be distinguished. The study summary describes an interest in increasing protection against tuberculosis, but the posted primary result is the percentage of subjects with an adverse event. Safety and immune-response outcomes can be important in an early-stage study, yet they answer different questions from a clinical tuberculosis outcome. The registry’s immune-response measures are listed as secondary outcomes, but results are not reported in the registry record.

The trial also provides an example of interpreting common binary outcomes. Adverse events were reported for most subjects in every group, leaving percentages clustered near the upper end of the scale. In that setting, reading only the arm percentages can obscure the uncertainty in comparisons. The confidence intervals for the listed risk differences are essential context, and each includes zero. This highlights the distinction between an observed point estimate and a precise estimate of a group contrast.

The common placebo reference also makes the comparison structure important. The risk differences are listed against the expanded safety placebo group, while dose-finding groups followed a two-dose schedule and expanded safety groups followed a three-dose schedule. Statistical interpretation therefore depends on understanding which treatment schedules and participants each comparison represents.

Finally, the record shows the value of reporting analysis details alongside results. Unadjusted comparisons are posted, but the multiplicity approach, original sample-size justification, detailed analysis populations, and missing-data procedures are not reported in the registry record. Those details help readers understand how estimates were selected, how uncertainty was handled, and how broadly results can be interpreted. Their absence does not erase the descriptive findings, but it limits the conclusions that can be drawn from them.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The posted primary endpoint is adverse-event reporting rather than a tuberculosis outcome. As a result, the primary results do not directly address whether the study intervention changed protection against tuberculosis. The registry lists immune-response and QuantiFERON outcomes, but does not report their results, leaving the study’s stated protection-related aim unresolved in the posted record.

Some key statistical details are not reported in the registry record. These include the original sample-size justification, the detailed statistical analysis plan, methods for handling missing data, and analysis populations beyond the stated primary endpoint population. The record also does not explain whether the analyses were prespecified or how multiplicity across outcomes and comparisons was handled. The p-values are unadjusted.

The reported comparisons use the expanded safety placebo group as the reference for the dose-finding groups as well as the expanded safety AERAS-402 group. The dose-finding and expanded safety groups had different vaccination schedules. The registry does not explain the rationale for this common reference or report analyses accounting for the schedule differences. This should be kept in mind when interpreting the comparisons as contrasts between groups.

Arm-level percentages do not have confidence intervals reported alongside them. Comparative confidence intervals are available, but the interval-construction method is not reported in the registry record. The listed serious-event terms also lack further denominator context in the posted summary, and death counts are not reported. Finally, event reporting does not by itself establish whether an event was related to vaccination. These limitations constrain interpretation without changing the descriptive values that are posted.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study of AERAS-402 in Healthy Infants — NCT01198366.
• Registry record last updated 2017-05-08; status last verified 2017-03.
• Results first posted 2015-08-04.
• 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

The registry record describes NCT01198366, “Study of AERAS-402 in Healthy Infants,” as a randomized, quadruple-masked, parallel-group study categorized as Phase I and Phase II. It reports enrollment of 487 and completed status. Participants were BCG-vaccinated, HIV-uninfected infants without evidence of tuberculosis.

The study included dose-finding groups receiving two scheduled doses of placebo or AERAS-402, and an expanded safety phase comparing three scheduled doses of AERAS-402 with three doses of placebo. The primary outcome was the percentage of vaccinated subjects with an adverse event, with serious adverse events recorded over the study period.

Reported adverse-event percentages were high across all groups. The listed risk-difference comparisons use the expanded safety placebo group as the reference, and their confidence intervals include zero. Secondary immune-response results, the original sample-size justification, multiplicity strategy, detailed missing-data methods, and further analysis-plan details are not reported in the registry record.