This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Immunogenicity and Safety Study to Assess Influenza Vaccine Formulated With Haemagglutinin (HA) Antigen From Two Different Suppliers (NCT01412281), a randomized phase 3 study. The primary outcome is Geometric Mean Titer.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01412281 |
| Phase | Phase 3 |
| Condition | Influenza |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 440 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Crucell Holland BV |
| Results posted | Yes |
2. Clinical Question
Population
The trial enrolled young adults aged ≥18 to ≤60 years and older adults aged >60 years. The registry lists 440 participants overall and describes four groups, with 110 participants at risk in each group for the reported adverse-event summaries. The primary endpoint population is described as vaccinated participants with available pre- and post-vaccination titers.
Intervention
Participants received a single 0.5 mL intramuscular dose of virosomal influenza vaccine formulated with AdImmune HA antigen. The arm descriptions identify this as the 2011/2012-season vaccine.
Comparator
The comparator was a single 0.5 mL intramuscular dose of virosomal influenza vaccine formulated with CSL HA antigen, also described in the arm descriptions as the 2011/2012-season vaccine. The comparison is made separately within the young-adult and older-adult groups.
Primary question
The trial assessed whether the two formulations differed in humoral immune response, measured using hemagglutinin-inhibition antibody titers. The primary endpoint was geometric mean titer and fold-increase in geometric mean titer from baseline, assessed 3 weeks after vaccination (Day 22 ± 2 days). Numerical primary-endpoint results are not reported in the registry record, so the magnitude and precision of the immune-response comparisons cannot be described from this record.
3. Trial Design
This was a randomized, parallel-group, double-blind, single-center Phase III study. Its stated aim was to assess immunogenicity and safety of a virosomal subunit influenza vaccine made with HA antigen from two suppliers, in young and elderly adults. The registry identifies Crucell Holland BV as the sponsor and lists influenza as the condition. The study status is completed. The recorded enrollment was 440, with the study starting in 2011-10 and primary completion in 2011-12.
Four groups combine age category and antigen supplier: young adults received either AdImmune or CSL HA antigen, and older adults received either AdImmune or CSL HA antigen. Each arm description specifies one 0.5 mL intramuscular dose. The adverse-event summaries list 110 participants at risk in each group. Although these group counts describe the safety summaries, the registry does not report participant flow, withdrawals, or the number included in each endpoint analysis.
The record has a season-label inconsistency. The official title and arm descriptions identify the 2011/2012-season vaccine, while the brief summary describes the vaccine as the 2010/2011-season formulation. The available record does not resolve that difference. The stated endpoint timing is 3 weeks after vaccination (Day 22 ± 2 days). The registry says the study used the EMA regulation as a guideline, and the endpoint description refers to the EMA note on harmonisation of requirements for influenza vaccines from 1997. Further protocol details, including the recruitment setting beyond the single-center designation, are not reported in the registry record.
The age-specific design matters for interpretation: the intended supplier comparison is not just one overall contrast, but a comparison within each age category. No combined estimate across age groups, adjustment strategy, or formal test of whether the supplier contrast differed by age is reported in the registry record. The primary endpoint is based on participants who were vaccinated and had both baseline and follow-up titers available, rather than necessarily every person enrolled.
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
| Stage | ≥18 to ≤60 Years - AdImmune HA Antigen | ≥18 to ≤60 Years - CSL HA Antigen | >60 Years - AdImmune HA Antigen | >60 Years - CSL HA Antigen |
|---|---|---|---|---|
| STARTED | 110 | 110 | 110 | 110 |
| COMPLETED | 110 | 110 | 110 | 110 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Intent-to-treat, vaccinated subjects with available pre- and post-vaccination titers
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.
| Characteristic | Unit | ≥18 to ≤60 Years - AdImmune HA Antigen | ≥18 to ≤60 Years - CSL HA Antigen | >60 Years - AdImmune HA Antigen | >60 Years - CSL HA Antigen | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 110 | 110 | 110 | 110 | 440 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 110 | 110 | 33 | 38 | 291 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 77 | 72 | 149 |
| Age Continuous | years | 39.6 (SD 12.46) | 42.5 (SD 11.98) | 68.4 (SD 5.86) | 67.8 (SD 5.31) | 54.6 (SD 16.56) |
| Sex: Female, Male: Female | Participants | 55 | 55 | 49 | 48 | 207 |
| Sex: Female, Male: Male | Participants | 55 | 55 | 61 | 62 | 233 |
| Region of Enrollment: Switzerland | participants | 110 | 110 | 110 | 110 | 440 |
6. Primary Endpoint
The registry lists the primary outcome as Geometric Mean Titer, measured over 3 weeks after vaccination (Day 22 ± 2 days).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | 95% Confidence Interval |
| Unit | GMT fold increase from baseline |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint concerns antibodies to influenza HA, measured by the hemagglutinin-inhibition (HI) method. The registry describes geometric mean titer (GMT) and fold-increase in GMT from baseline as the primary immunogenicity parameters. Measurements were scheduled 3 weeks after vaccination (Day 22 ± 2 days), and the population is described as vaccinated participants with available titers before and after vaccination.
General statistical explanation: antibody titers are often summarized with a geometric mean because they can vary multiplicatively and may have a skewed distribution on the original scale. A geometric mean reflects the central level after working on a logarithmic scale, then expressing the summary back on the original scale. A fold-increase compares a follow-up summary with its baseline value, expressing change as a multiplicative relation rather than an absolute difference. Neither measure alone describes every participant’s response.
Confidence intervals communicate uncertainty around an estimate. A narrower interval indicates greater precision under the analysis assumptions; a wider interval indicates more uncertainty. The registry identifies a 95% confidence interval as the dispersion measure, but it does not report the GMT estimates, fold-increases, confidence limits, or numerical comparisons. Consequently, the endpoint definition and timing are known, but the observed immune-response levels and their precision are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes a comparison of two vaccine formulations that differ by the supplier of their HA antigen, with the comparison considered in young and older adults. The study was randomized and double-blind, features intended to reduce systematic differences in treatment assignment and expectations. However, design labels do not substitute for outcome estimates. The record does not report the primary GMT results or fold-increases, nor their 95% confidence intervals. It therefore does not establish how similar or different the measured antibody responses were between formulations.
The primary endpoint is an immune-response measure assessed at 3 weeks after vaccination (Day 22 ± 2 days). Its stated analysis population consists of vaccinated participants with available pre- and post-vaccination titers. The number of people meeting that endpoint-population definition is not reported in the registry record. Enrollment and the number at risk in each safety group do not establish how many had complete titers for the primary analysis.
It is also not possible to assess statistical uncertainty or practical importance from endpoint definitions alone. An estimate would describe the observed response under the specified analysis, while its confidence interval would indicate the precision of that estimate. No estimate, interval, p-value, or explicit supplier-comparison result appears in the registry record. The absence of those quantities should not be interpreted as evidence that the groups were equivalent, or that one formulation had a larger response.
The record names an EMA guideline as a reference for analysis, but it does not report the decision criteria used to interpret the immunogenicity results. A guideline reference alone does not reveal which endpoints were evaluated against which thresholds, how age groups were handled, or how uncertainty was incorporated. These details are not reported in the registry record.
Safety information is available in the form of counts of participants affected by adverse events. The serious-event count is zero in three groups and one in the older CSL-antigen group. The record also gives counts for participants with other adverse events. These are descriptive counts, not a complete comparative safety analysis: timing, severity grading beyond the serious-event distinction, exposure-adjusted rates, and statistical comparisons are not reported in the registry record. A single serious-event count cannot by itself establish whether an event was caused by vaccination.
The record’s mismatch between the 2011/2012 season in the official title and arm descriptions and the 2010/2011 season in the brief summary further limits certainty about the exact formulation label. This inconsistency does not change the reported group structure or endpoint timing, but the registry does not resolve it. Overall, the available information supports describing the design, endpoint, and posted safety counts; it does not support a numerical conclusion about comparative immunogenicity or a causal conclusion about safety.
9. Statistical Methods Explained
What does a geometric mean summarize?
General statistical explanation: a geometric mean is suited to measurements whose values are naturally interpreted on a multiplicative scale. The calculation uses logarithms to summarize the values and then transforms the summary back. This can be useful for antibody titers, which may be distributed unevenly on their original scale. A GMT is a group-level summary, not an assertion that every participant had that titer. The registry names GMT and fold-increase in GMT from baseline as primary immunogenicity parameters, but does not report the estimates or the exact computational details used for the trial analysis.
What is the role of a confidence interval?
General statistical explanation: a confidence interval describes the range of values compatible with an estimate under the model and assumptions used. Its width conveys precision: less precision is reflected by a wider interval. The registry specifies 95% confidence intervals as the measure of dispersion for the endpoint. Since neither estimates nor interval limits are reported, the precision of the immune-response findings cannot be assessed. A confidence interval also does not remove the need to consider the analysis population, missing measurements, endpoint definition, and whether the statistical model is suitable.
Why is the endpoint assessed after vaccination?
The recorded follow-up time is 3 weeks after vaccination (Day 22 ± 2 days). The endpoint includes both GMT and its fold-increase from baseline, so it is framed around post-vaccination titers and their relation to pre-vaccination measurements. General statistical explanation: using a baseline measure can help describe how a group’s titers changed over time, while a post-vaccination comparison describes the measured antibody level at follow-up. The registry does not specify whether the supplier comparisons were based on post-vaccination values, fold-increases, or both in a particular decision rule. It also does not report a model adjusting for baseline titers.
What is meant by over-dispersion?
General statistical explanation: over-dispersion occurs when observed variability exceeds what a statistical model’s assumptions would predict. It can make standard errors too small if the model does not account for the extra variability, leading to confidence intervals that are too narrow and tests that appear more decisive than warranted. This concept is relevant in some count-data analyses, but the primary endpoint is a titer summary, and the registry does not report an analysis model or a finding of over-dispersion. No claim about its presence or handling can be made for this trial.
What does the design contribute?
Random assignment is intended to make treatment groups comparable with respect to factors known and unknown at enrollment. Double masking is intended to limit influence from knowledge of the assigned formulation on participant reports or study conduct. A parallel-group design means participants are assigned to a group and assessed within that group rather than crossing between formulations. These are general design principles; the registry does not provide details on sequence generation, concealment, who was masked, or how masking was maintained. The single-center designation identifies the study setting at a broad level but does not describe the center or recruitment procedures.
How should planning calculations be read?
The planning assumptions describe an illustration based on an observed effect, not the trial’s original design justification. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. For time-to-event settings, the stated convention is total events, while other settings use participants per arm. This trial’s primary endpoint is not presented as a time-to-event outcome. These assumptions do not provide evidence that the trial had a particular probability of detecting an effect, and planning illustrations are not observed power. The registry does not report the original sample-size justification, the effect targeted when the trial was planned, or the planning calculations’ resulting participant counts in the record.
More generally, an observed-effect-based planning illustration depends on the estimated effect used as its starting point. When endpoint estimates are absent, the illustration cannot be used to recover the trial’s observed result. It should be distinguished from a prospectively specified sample-size calculation, which would be based on design assumptions chosen before observing outcomes. The registry record does not report whether such a prospective calculation was conducted or what assumptions it used.
10. Multiplicity, Missing Data and Analysis Populations
The primary endpoint description includes GMT and fold-increase in GMT, while the record lists four outcome measures and identifies a safety outcome concerning participants with local and systemic adverse events. It does not report how many primary comparisons were formally tested, whether the two age-specific supplier comparisons were treated as separate hypotheses, or whether any adjustment for multiple comparisons was used. Multiplicity methods and any hierarchy or order of testing are not reported in the registry record.
Missing data are important because the primary population is defined as vaccinated participants with available pre- and post-vaccination titers. The registry does not report how many participants lacked either measurement, why data were missing, or whether missingness differed by group. It also does not describe imputation, sensitivity analyses, or other methods for handling incomplete titers. The number enrolled and the numbers at risk in safety summaries do not reveal the endpoint-specific analysis counts.
The registry names the intent-to-treat, vaccinated population with available titers for the primary endpoint. It does not give a more detailed definition of intent-to-treat, report a separate per-protocol population, or state which population was used for each analysis. The number of analyses reported in the available record is zero. The statistical analysis plan, interim analyses, and protocol-level rules for exclusions or deviations are not reported in the registry record. These gaps prevent assessment of whether the reported endpoint analyses, if any, followed a prespecified plan or how robust they were to alternative population definitions.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| ≥18 to ≤60 Years - AdImmune HA Antigen | 0 | 110 | 0.0% |
| ≥18 to ≤60 Years - CSL HA Antigen | 0 | 110 | 0.0% |
| >60 Years - AdImmune HA Antigen | 0 | 110 | 0.0% |
| >60 Years - CSL HA Antigen | 1 | 110 | 0.9% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| ≥18 to ≤60 Years - AdImmune HA Antigen | 60 of 110 |
| ≥18 to ≤60 Years - CSL HA Antigen | 52 of 110 |
| >60 Years - AdImmune HA Antigen | 33 of 110 |
| >60 Years - CSL HA Antigen | 29 of 110 |
Most frequent serious adverse event terms
| Event term | Organ system | ≥18 to ≤60 Years - AdImmune HA Antigen | ≥18 to ≤60 Years - CSL HA Antigen | >60 Years - AdImmune HA Antigen | >60 Years - CSL HA Antigen |
|---|---|---|---|---|---|
| Tibia fracture | Injury, poisoning and procedural complications | 0 of 110 | 0 of 110 | 0 of 110 | 1 of 110 |
Most frequent non-serious adverse event terms
| Event term | Organ system | ≥18 to ≤60 Years - AdImmune HA Antigen | ≥18 to ≤60 Years - CSL HA Antigen | >60 Years - AdImmune HA Antigen | >60 Years - CSL HA Antigen |
|---|---|---|---|---|---|
| Pain (at the injection site) | General disorders | 44 of 110 | 31 of 110 | 18 of 110 | 12 of 110 |
| Erythema (at the injection site) | General disorders | 11 of 110 | 7 of 110 | 6 of 110 | 9 of 110 |
| Headache | Nervous system disorders | 8 of 110 | 9 of 110 | 2 of 110 | 2 of 110 |
| Induration (at the injection site) | General disorders | 6 of 110 | 6 of 110 | 2 of 110 | 4 of 110 |
| Malaise | General disorders | 6 of 110 | 8 of 110 | 2 of 110 | 1 of 110 |
| Nasopharyngitis | Infections and infestations | 4 of 110 | 4 of 110 | 7 of 110 | 2 of 110 |
| Rhinitis | Infections and infestations | 7 of 110 | 5 of 110 | 1 of 110 | 2 of 110 |
| Pyrexia | General disorders | 1 of 110 | 2 of 110 | 3 of 110 | 2 of 110 |
| Diarrhoae | Gastrointestinal disorders | 1 of 110 | 3 of 110 | 2 of 110 | 0 of 110 |
| Chills | General disorders | 3 of 110 | 2 of 110 | 0 of 110 | 0 of 110 |
Serious events with the highest arm-level rate: tibia fracture (0.9%).
The adverse-event summaries list 110 participants at risk in each of the four groups. The serious adverse-event counts are 0 among young adults receiving AdImmune HA antigen, 0 among young adults receiving CSL HA antigen, 0 among older adults receiving AdImmune HA antigen, and 1 among older adults receiving CSL HA antigen. The record also lists tibia fracture at 0.9% among the top serious terms. The registry does not give further event-level detail in the information.
These figures count participants affected, not necessarily the total number of individual events. The record separately reports other adverse-event counts of 60, 52, 33, and 29 for the same groups, respectively. These counts should not be read as serious-event counts. The registry does not report the timing, duration, severity grading for events outside the serious category, or whether events were considered related to vaccination.
A serious-event count is descriptive. It does not establish cause, and the single reported affected participant does not by itself support a comparative safety conclusion. Deaths are not reported in the registry record; a missing death value should not be read as a reported zero. Safety comparisons would also require information about ascertainment, follow-up, and analysis methods, which are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a randomized, double-blind, parallel-group study compared virosomal influenza vaccines using HA antigen from AdImmune and CSL in young and older adults. It specifies the primary immune-response measures, the follow-up time, the endpoint population definition, and the number of participants at risk in each safety group. These registry entries describe what the study set out to assess and how its main outcome was defined.
The record does not report the numerical GMTs, fold-increases, confidence intervals, or statistical comparisons. As a result, it cannot show the size or precision of any difference in immune response between the formulations. A lack of numerical findings in the registry record is not evidence that there was no difference, nor is it evidence of equivalence. Equivalence or non-inferiority conclusions require an explicit framework and results against prespecified criteria; these are not reported in the registry record.
The safety counts show that the registry recorded one participant with a serious adverse event in the older CSL-antigen group and none in the other three groups. They also show the reported counts for participants with other adverse events. Those observations describe the posted counts only. They do not establish that a vaccine caused an event, and the limited information does not support a balanced comparison of risks over time.
The result therefore has a clear boundary: the design and outcome definitions are documented, but the primary outcome findings are not. The record cannot answer whether antibody responses were similar across suppliers, whether any difference was precise, or whether an observed difference met a regulatory criterion. It also cannot establish the cause of the serious event or interpret the missing death values as zero. Those questions require results and analysis details that are not reported in the registry record.
13. Why This Trial Matters Statistically
This trial raises a useful statistical question about comparing formulations within age categories. Its four-group structure distinguishes the supplier comparison in young adults from the supplier comparison in older adults. That structure makes clear why an overall summary alone might not answer every relevant question: age category is part of the design, and interpretation may depend on whether the supplier contrast is consistent across the groups. The registry does not report estimates for either age-specific comparison or a formal assessment of differences between them.
The endpoint also illustrates why statistical summaries need their definitions and uncertainty alongside them. GMT and fold-increase describe antibody responses on a multiplicative scale, while a confidence interval would indicate how precisely those responses were estimated. Without numerical values and intervals, readers cannot judge the observed pattern or distinguish a precisely estimated result from a highly uncertain one. An endpoint name and a scheduled assessment time are not results.
The safety information offers a separate lesson in reading sparse events. A serious-event count of one in one group and zero in the others is a description of recorded participants, not proof of a treatment effect. Attribution, follow-up, and context are needed before drawing causal conclusions. Missing death values likewise cannot be converted into a claim of zero deaths.
Finally, the season-label mismatch is a reminder that registry fields may not be internally consistent. The official title and arm descriptions say 2011/2012, while the brief summary refers to 2010/2011. Recording that ambiguity is more informative than silently choosing one label. Taken together, this study illustrates how design features, endpoint definitions, analysis populations, uncertainty, and record completeness all shape the conclusions that can responsibly be drawn.
14. 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 most important limitation for interpretation is that numerical primary-endpoint results are not reported in the registry record. GMT estimates, fold-increases, confidence intervals, and supplier comparisons are absent, so neither effect magnitude nor precision can be assessed. The registry also does not report the endpoint-specific analysis counts or the number of participants with complete pre- and post-vaccination titers.
There is a season discrepancy: the official title and arm descriptions identify the 2011/2012 season, but the brief summary describes the 2010/2011-season vaccine. The record does not explain whether this is a wording error or reflects a difference in the formulation description. This leaves uncertainty about the season label, although the administered dose and supplier groups are specified.
Several design and analysis details are not reported in the registry record, including randomization procedures, masking implementation, detailed analysis methods, handling of missing data, multiplicity procedures, and the original sample-size justification. The record does not describe participant flow, protocol deviations, or whether additional analyses were planned. It also does not provide enough safety detail to evaluate event timing, attribution, or duration, and deaths are not reported in the registry record.
The study is identified as single-center and randomized, but the registry information does not establish how broadly results would apply beyond the enrolled groups and setting. The stated age categories and available safety counts define the reported groups; details about other participant characteristics are not reported in the registry record. These limitations restrict both comparative interpretation and assessment of generalizability.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Immunogenicity and Safety Study to Assess Influenza Vaccine Formulated With Haemagglutinin (HA) Antigen From Two Different Suppliers — NCT01412281.
- Registry record last updated 2013-09-09; status last verified 2013-08.
- Results first posted 2013-03-22.
- 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.
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18. Record Summary
NCT01412281 is a completed randomized, double-blind, parallel-group Phase III study sponsored by Crucell Holland BV. It enrolled 440 participants and compared virosomal influenza vaccine formulations made with AdImmune or CSL HA antigen among young adults aged ≥18 to ≤60 years and older adults aged >60 years. The arm descriptions specify a single 0.5 mL intramuscular dose and identify the 2011/2012 season, while the brief summary refers to the 2010/2011 season.
The primary endpoint was GMT and fold-increase in GMT from baseline, measured by HI at 3 weeks after vaccination (Day 22 ± 2 days), among vaccinated participants with available pre- and post-vaccination titers. Numerical primary-endpoint findings are not reported in the registry record. The adverse-event summaries list 110 participants at risk in each group, with one serious adverse-event-affected participant in the older CSL group and none in the other groups. The registry does not report deaths or detailed comparative safety analyses.