A Study to Evaluate Safety and Immune Response of Novartis Meningococcal ACWY Vaccine In Healthy Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate Safety and Immune Response of Novartis Meningococcal ACWY Vaccine In Healthy Adults (NCT00474487), a randomized phase 3 study. The primary outcome is Number of Subjects With at Least One Severe Systemic Reaction, Ages 19 to 55 Years.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, double-masked, parallel-group study. The official title describes it as multi-center. The registry records enrollment of 2831 and a completed study, with a start date of 2007-05 and primary completion in 2007-08. The study evaluated safety and immune response for a Novartis meningococcal ACWY conjugate vaccine and included comparisons with licensed vaccines.

The age groups and comparators differed. For ages 19 to 55 years, the registry describes the Novartis vaccine and a licensed conjugate vaccine. For ages 56 to 65 years, it describes the Novartis vaccine and a licensed polysaccharide vaccine. The primary endpoint concerns participants aged 19 to 55 years and compares the Novartis vaccine with the licensed conjugate vaccine. The older-age comparison is not the primary endpoint comparison.

The record’s brief summary refers to healthy adolescents and adults, while the official title and listed age groups describe adults aged 19 to 65 years. The primary endpoint description specifically identifies healthy participants aged 19 to 55 years. These details identify the registry’s stated populations and comparisons; further eligibility criteria are not reported in the registry record.

The record lists six secondary outcomes, covering seroresponse and hSBA levels by age group, as well as local and systemic reactions. It does not report numerical results for those secondary outcomes in the registry record for this analysis. Further information about randomization procedures, masking procedures, vaccine schedules beyond the single vaccination stated for the primary endpoint, or the original design assumptions is 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: All subjects enrolled were included in the trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the safety set. The number of subjects in the safety set is less than the randomized set due to premature withdrawals.

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 Subjects With at Least One Severe Systemic Reaction, Ages 19 to 55 Years, measured over Days 1 to 7.

The primary endpoint counts participants aged 19 to 55 years who had at least one severe systemic reaction during Days 1 to 7 after a single vaccination. It is a participant-level binary outcome: each participant is counted according to whether the event occurred at least once in the specified period. The reported values are counts of participants, not counts of every reaction episode.

A short, defined observation window makes the safety outcome interpretable for reactions following vaccination. Counting participants with at least one event also avoids treating repeated reactions in one participant as if they came from separate participants. This is a general feature of participant-level binary endpoints; it does not describe how often an individual participant experienced repeated events.

The endpoint addresses a specific aspect of safety and is not a measure of immune response. The registry lists immune-response outcomes separately, including seroresponse and hSBA measures. Nor does this endpoint capture every possible safety outcome or establish the cause of an event. The registry describes the analysis as being performed on the safety set, which was smaller than the randomized set because of premature withdrawals. The number of participants with an event and the safety-set denominator are reported separately for each group.

7. Results Posted in the Registry

• Licensed Conjugate Vaccine: 5.2% (46/882) versus 6.0% (95/1588) on control; risk difference -0.8 percentage points (95% CI -2.6 to 1.1), risk ratio 0.87 (0.62–1.23); unadjusted two-proportion z-test p = 0.431.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the endpoint count?

The endpoint is a binary participant-level outcome. A participant either had at least one severe systemic reaction during Days 1 to 7 or did not. The reported event counts are 95 participants in the Novartis group and 46 in the licensed conjugate group; their corresponding analysis denominators are 1588 and 882. In general, a binary endpoint can be summarized by the proportion of participants with the event. These group proportions are reported as 0.060 and 0.052.

This endpoint counts participants with any qualifying event in the window, rather than adding repeated events within the same participant. That distinction matters: an event count and a count of affected participants answer different questions. The registry’s stated unit is subjects, and its description refers to subjects presenting at least one severe systemic reaction.

How should the risk difference be read?

The risk difference subtracts one group’s event proportion from the other’s. The comparison is expressed as licensed conjugate vaccine minus Novartis vaccine. Its reported estimate is -0.008. Under this direction, a negative value means the observed proportion was lower in the licensed conjugate group. The size of the estimate is an absolute difference on the proportion scale; it is not a relative percentage change.

Risk differences are often useful for clinical interpretation because they express the gap between group proportions directly. They can also be sensitive to the baseline frequency of the outcome and to sampling uncertainty. A point estimate alone does not show how precisely the difference has been estimated, so it should be read alongside its interval and the study’s analysis context.

What do the relative measures add?

The registry also reports a risk ratio estimate of 0.872, with an interval from 0.619 to 1.228, and an odds ratio estimate of 0.865, with an interval from 0.602 to 1.242. These measures compare groups on relative rather than absolute scales. A ratio of one represents no relative difference. Both reported intervals include that value, so neither relative summary isolates a clear difference in this comparison.

Risk ratios compare proportions directly. Odds ratios compare the odds of an event, which are not the same as event proportions. The two ratios can differ, especially when an outcome is not rare. The reported estimates should therefore be interpreted according to their own scales rather than treated as interchangeable. Neither ratio by itself describes the absolute number of affected participants.

What does the p-value say?

The unadjusted p-value is 0.431. In general, a p-value describes how compatible the observed data are with a specified statistical model in which there is no group difference, under the assumptions of the test. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a difference. A p-value also does not show whether a study was designed to establish equivalence or non-inferiority.

The registry does not report the detailed statistical test or model used for the sponsor’s primary analysis. The p-value should therefore be treated as the posted unadjusted result, not as a basis for assuming undocumented modeling choices. The interval and the observed group summaries offer complementary descriptions of the comparison.

Why is the interval important?

A confidence interval expresses uncertainty around an estimated effect. In general, it describes a range of effect values reasonably compatible with the data and the method used to construct it. The interval for the risk difference, -0.026 to 0.011, includes zero. It is therefore consistent with no difference as well as with differences in either direction over the values covered by the interval. Its breadth is relevant: the data do not pinpoint the risk difference precisely.

Intervals are not guarantees that the true effect lies within the reported range, and their interpretation depends on the statistical method and assumptions. The registry does not report all details needed to independently reconstruct the sponsor’s analysis. For a binary endpoint, uncertainty depends on the event counts and group denominators; small event counts can make estimates less precise. This is a general statistical consideration, not a claim about an unreported analysis procedure.

What do the planning figures represent?

The separate planning illustration uses the observed effect as a reference and considers detecting stated fractions of that effect. It assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Because this is not a time-to-event outcome, the reported planning values are participants per arm. The illustration is not the original trial design calculation; the original design assumptions are not reported in the registry record.

10. Confidence Intervals and Precision

The risk-difference estimate is -0.008, and its reported interval extends from -0.026 to 0.011. The range includes zero, the value representing no absolute difference between the group proportions. It also extends to values on either side of zero, so the observed data are compatible with a lower proportion in either group. The interval is a more complete description of precision than the point estimate alone.

The risk ratio is 0.872, with an interval from 0.619 to 1.228. The odds ratio is 0.865, with an interval from 0.602 to 1.242. Each relative interval includes one, its no-difference value. These ranges are fairly broad relative to their point estimates and do not identify a single narrow relative effect. They should be read on their own scales and alongside the absolute risk difference.

In general, confidence intervals reflect sampling uncertainty under the method used to construct them. They are not a guarantee about the true effect, and they do not measure every source of uncertainty, such as limitations in outcome ascertainment or analysis choices. The registry does not report the detailed method used to calculate these intervals, so further assumptions about their construction are not warranted.

The endpoint involved 95 events in the Novartis group and 46 in the licensed conjugate group. Event counts and denominators both inform precision for a binary outcome. The interval’s inclusion of no difference, together with its range, means the observed estimate should not be treated as a precise measure of a group difference. This is distinct from saying that the groups are equivalent: no equivalence margin is reported in the registry record.

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 illustration reports participants per arm, not total events. It applies to this binary participant-level outcome, rather than a time-to-event outcome. The stated assumptions 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 to a stated fraction of the observed effect. The registry’s original sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the estimated number of participants per arm for a planning scenario designed to have an 80% chance of detecting the specified effect if that effect were the true one and the assumptions held. The 90% power column gives the corresponding planning number for a 90% chance. These are design illustrations, not guarantees about a future study’s results. They depend on the stated assumptions and the effect size used in each row.

For planning at 100% of the observed effect, the illustration gives 14,105 participants per arm for 80% power and 18,882 participants per arm for 90% power. Planning for 75% of the observed effect gives 25,479 participants per arm for 80% power and 34,109 participants per arm for 90% power. Planning for 50% of the observed effect gives 58,235 participants per arm for 80% power and 77,959 participants per arm for 90% power. Smaller effects require more participants under these assumptions because they are harder to distinguish from random variation.

These values are planning illustrations based on the observed effect, not observed power for the completed trial. They should not be interpreted as evidence about the trial’s original planning or as a post hoc measure of what the trial achieved.

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 = 0.060; treatment proportion p₁ = 0.052; average p̄ = 0.056.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3251 = 0.6372.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3251 = 0.2736.
4. n = (0.6372 + 0.2736)² / (-0.0077)² = 14,104.2, rounded up to 14,105 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 <- 0.059823677581864                          # control proportion
p1 <- 0.0521541950113379                          # 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(474487)
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 = 14,105 (80% power), 18,882 (90% power)
 75% of observed effect: n per arm = 25,479 (80% power), 34,109 (90% power)
 50% of observed effect: n per arm = 58,235 (80% power), 77,959 (90% power)
power.prop.test: 14104.2 
Simulated power at n = 14,105 per arm: 0.794 (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 six secondary outcomes in addition to the primary endpoint. They cover seroresponse and hSBA outcomes for ages 19 to 55 years and ages 56 to 65 years, as well as local and systemic reactions in each age group. When several outcomes are examined, the chance of at least one apparently unusual result can increase. In general, multiplicity methods can control that risk, but the appropriate approach depends on which hypotheses were planned and how they were ordered or grouped.

Multiplicity adjustment procedures, a testing hierarchy, and any prespecified primary or secondary analysis strategy beyond the named primary endpoint are not reported in the registry record. The posted p-value is identified as unadjusted. It should not be described as adjusted for the secondary outcomes, and the record does not support an assumption that such adjustment was or was not used elsewhere.

The endpoint description states that the primary analysis used the safety set. That set was smaller than the randomized set because of premature withdrawals. The safety-set denominators for this comparison are 1588 for the Novartis vaccine and 882 for the licensed conjugate vaccine. The registry does not report the number or reasons for withdrawals in the primary endpoint description, the handling of missing endpoint data, or a sensitivity analysis for missing outcomes. Those details are not reported in the registry record.

The record lists secondary immune-response outcomes for a per-protocol population, but numerical results for those outcomes are not available in the registry record. The per-protocol population definition, exclusions, and missing-data rules are not reported in the registry record. In general, analyses using different populations may answer somewhat different questions, and population definitions matter for interpretation.

Although the study is described as randomized and double-masked, the registry does not provide the detailed randomization, allocation-concealment, masking, or analysis procedures in the record. Nor does it report interim analyses or a full statistical analysis plan. These omissions limit the ability to assess prespecification and the treatment of missing data or multiple comparisons beyond what the posted endpoint and result state.

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: pyometra (0.9%), hypovolaemic shock (0.5%), abortion spontaneous (0.2%), abdominal pain (0.1%), generalised oedema (0.1%).

For serious adverse events, the registry reports 11 affected participants among 1588 at risk in the Novartis MenACWY group aged 19 to 55 years, and 8 among 882 at risk in the licensed conjugate group aged 19 to 55 years. In the older-age groups, it reports 1 among 216 for the Novartis vaccine and 1 among 109 for the licensed polysaccharide vaccine. These are safety summaries across the listed groups; the registry does not establish that the groups are directly comparable for every safety analysis.

The serious adverse event figures are distinct from the primary endpoint, which counts severe systemic reactions during Days 1 to 7. The registry also lists other adverse-event counts: 955 among 1588, 124 among 216, 561 among 882, and 62 among 109 for the respective groups. These figures should not be confused with the serious-event counts.

The listed serious-event terms include Pyometra, Hypovolaemic Shock, Abortion Spontaneous, Abdominal Pain, Generalised Oedema, and Cellulitis, with percentages shown in the registry record. The registry does not report deaths in the registry record; that absence is not evidence that there were no deaths. These summaries do not by themselves establish causation.

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

The posted primary endpoint results describe the frequency of participants aged 19 to 55 years who experienced at least one severe systemic reaction during Days 1 to 7 after vaccination. The observed proportions were 0.060 for the Novartis vaccine and 0.052 for the licensed conjugate vaccine. The estimated risk difference was -0.008 for licensed conjugate vaccine minus Novartis vaccine, with an interval from -0.026 to 0.011 and an unadjusted p-value of 0.431.

These data show a modest observed separation between the group summaries, but the interval includes zero and permits effects in either direction. The result therefore does not provide a clear statistical distinction for this endpoint. That is not the same as demonstrating that the vaccines have equal risks, nor does it establish equivalence or non-inferiority. Such conclusions require an appropriate prespecified design and margin, which are not reported in the registry record.

The endpoint has a limited scope. It concerns severe systemic reactions, a specified short follow-up window, and participants aged 19 to 55 years. It does not summarize every safety outcome, long-term outcomes, immune response, or the separate comparison among participants aged 56 to 65 years. The registry lists immune-response and reaction outcomes as secondary measures, but their numerical results are not reported in the registry record.

The results are based on the safety set rather than the randomized set, and the registry notes that premature withdrawals account for the smaller safety set. The record does not provide further detail about missing outcome data or the analysis methods. Interpretation should therefore remain tied to the posted groups, endpoint, and available precision, rather than extending to broader claims about overall safety or immune response.

16. Why This Trial Matters Statistically

This trial illustrates why a safety comparison needs more than a count of affected participants. The endpoint counts participants with at least one severe systemic reaction, while the accompanying denominators show the size of each safety set. Reporting both allows the observed group proportions to be interpreted in context. The risk difference then expresses the absolute contrast, while risk and odds ratios describe the comparison on relative scales.

It also shows why precision matters when the point estimate appears to favor one group on the measured scale. The risk-difference interval includes zero and extends in both directions; the relative intervals include one. The unadjusted p-value of 0.431 does not resolve that uncertainty or establish equivalence. A statistically inconclusive comparison is not proof that the groups are the same.

The design includes age-specific comparator groups: a licensed conjugate vaccine for participants aged 19 to 55 years and a licensed polysaccharide vaccine for participants aged 56 to 65 years. Keeping those comparisons distinct is important because the primary endpoint result applies only to the younger age-group comparison. Pooling or casually comparing the separate age groups would not be justified by the posted primary result.

Finally, the record illustrates the difference between observed results and planning calculations. The planning figures use the observed effect under explicit assumptions, but they are not the trial’s original design rationale or a measure of observed power. The record does not report the original sample-size assumptions, a detailed multiplicity strategy, or key missing-data procedures. Those absences constrain what can be concluded from registry summaries, even when the endpoint counts and effect estimates are available.

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 result is limited to a short safety window, Days 1 to 7, and to participants aged 19 to 55 years. It does not represent all adverse events, outcomes after that window, or the older-age comparison. The registry describes the analysis population as the safety set and notes that premature withdrawals made it smaller than the randomized set, but further information about withdrawals and missing endpoint data is not reported in the registry record.

The detailed statistical analysis method, confidence-interval construction, and any adjustment for multiple testing are not reported in the registry record. The unadjusted p-value is available, but the full analysis plan and the rationale for selecting the endpoint are not. An original sample-size justification, interim analyses, and a prespecified equivalence or non-inferiority margin are also not reported in the registry record.

The record lists secondary immune-response and safety outcomes, but numerical results for those outcomes are not included in the registry record. This limits interpretation of the study beyond the primary endpoint. The registry also does not provide enough detail in the record to assess the definitions and ascertainment procedures for every event category, or to determine how missing data were handled in the secondary outcomes.

The reported event counts and estimates are descriptive of the posted comparison, not proof of causation or a complete characterization of safety. The interval around the risk difference includes zero and is compatible with effects in either direction. The result should therefore be interpreted with its uncertainty and restricted to the population, comparator, endpoint, and follow-up period specified in the registry.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Evaluate Safety and Immune Response of Novartis Meningococcal ACWY Vaccine In Healthy Adults — NCT00474487.
• Registry record last updated 2014-04-21; status last verified 2014-04.
• Results first posted 2010-08-04.
• 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

NCT00474487 is a completed, randomized, double-masked, parallel-group Phase 3 study of meningococcal ACWY vaccines. The registry records enrollment of 2831, a start date of 2007-05, and primary completion in 2007-08. The primary safety endpoint counts participants aged 19 to 55 years with at least one severe systemic reaction during Days 1 to 7.

The posted comparison reports 95 of 1588 participants in the Novartis vaccine group and 46 of 882 in the licensed conjugate vaccine group with an event. The risk difference is -0.008, with an interval from -0.026 to 0.011 and an unadjusted p-value of 0.431. The registry also lists secondary immune-response and safety outcomes, but their numerical results are not reported in the registry record. The original design assumptions and several analysis details are not reported in the registry record.