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 Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid IMVAMUNE® (1x10^8 TCID50) Administered Subcutaneously and a Lower Dose Liquid IMVAMUNE® (2x10^7 TCID50) Administered Intradermally (NCT00914732), a randomized phase 2 study. The primary outcome is Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00914732 |
| Phase | Phase 2 |
| Condition | Smallpox |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 523 |
| Arms in the primary outcome | 2 |
| Lead sponsor | National Institute of Allergy and Infectious Diseases (NIAID) |
| Results posted | Yes |
2. Clinical Question
Population
The trial enrolled healthy, vaccinia-naïve individuals, as described in the official title. The registry summary describes adults aged 18 or older, born after 1971, with no prior smallpox vaccination. The registry reports enrollment of 523.
Intervention
The primary comparison concerns two doses of lyophilized IMVAMUNE® at 1x10^8 TCID50, administered subcutaneously on Day 0 and 28.
Comparator
The comparator was two doses of liquid IMVAMUNE® at 1x10^8 TCID50, also administered subcutaneously on Day 0 and 28. A third group received liquid IMVAMUNE® at 2x10^7 TCID50 intradermally.
Primary question
Among participants in the intention-to-treat immunogenicity population, what were the geometric mean titers based on individual peak vaccinia-specific PRNT results after the lyophilized formulation versus the liquid formulation, both given subcutaneously? The registry specifies assessments on Days 14, 28 and 180 after the second vaccination.
The clinical question is about comparative immunogenicity, not only whether either group generated an immune response. The primary endpoint compares titers between the lyophilized and liquid subcutaneous groups. The intradermal group used a lower dose and a different route, but it is not part of the posted primary comparison. Its presence is relevant to the broader trial, whose stated purpose included comparing safety and immunogenicity across formulations, doses and routes.
The registry describes the study as a phase 2, randomized, triple-masked, parallel trial. The reported primary analysis uses participants analyzed as randomized and is labelled ITT. A detailed account of how masking was implemented, or of who remained masked, is not reported in the registry record. The clinical question is therefore best read narrowly: it concerns the posted PRNT geometric mean titer comparison for the two subcutaneous formulations in the stated analysis population and at the listed assessment times.
3. Trial Design
This was a phase 2 randomized, triple-masked, parallel trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The registry status is completed. The recorded start was 2010-02, and primary completion was 2011-04. The registry reports enrollment of 523. Its brief summary separately describes approximately 495 adults as potential participants; the reason for that difference from the recorded enrollment is not reported in the registry record.
Three groups received IMVAMUNE®. Group A received the lyophilized formulation, 1x10^8 TCID50/0.5 mL per dose, subcutaneously. Group B received the liquid formulation at the same dose and volume by the subcutaneous route. Group C received the lower-dose liquid formulation, 2x10^7 TCID50/0.1mL per dose, intradermally. Each group description specifies a two-dose regimen on Day 0 and 28. The primary outcome compares Group A with Group B; it does not directly compare all three groups.
The condition listed is Smallpox. The official title describes healthy vaccinia-naïve individuals, and the brief summary describes adults aged 18 or older, born after 1971, who had not previously received smallpox vaccine. The registry record does not report additional eligibility details in the registry record for this analysis.
Randomization supports a comparison of groups formed by assignment, while the parallel design means participants were assigned to a group rather than receiving each formulation in turn. The registry labels masking as triple, but further operational details are not reported in the registry record. The registry entries also do not describe allocation concealment, the randomization sequence, protocol deviations, or the specific statistical plan. Those details should not be inferred from the design labels alone.
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 | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal |
|---|---|---|---|
| STARTED | 165 | 167 | 191 |
| Received Second Vaccination | 150 | 157 | 153 |
| COMPLETED | 155 | 160 | 180 |
| NOT COMPLETED | 10 | 7 | 11 |
Reasons for not completing this period:
| Reason | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal |
|---|---|---|---|
| Lost to Follow-up | 6 | 7 | 9 |
| Withdrawal by Subject | 3 | 0 | 2 |
| Adverse Event | 1 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The ITT analysis population for the immunogenicity summaries include all participants with results for the visit. Participants were analyzed as randomized. Not receiving the second vaccination or second vaccination being out of window was not considered.
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 | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal | Total |
|---|---|---|---|---|---|
| Participants analysed | 165 | 167 | 191 | 523 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 165 | 167 | 191 | 523 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 |
| Age, Continuous | years | 27.0 (SD 4.4) | 26.8 (SD 4.5) | 27.7 (SD 4.9) | 27.2 (SD 4.6) |
| Sex: Female, Male: Female | Participants | 81 | 80 | 102 | 263 |
| Sex: Female, Male: Male | Participants | 84 | 87 | 89 | 260 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 6 | 17 | 12 | 35 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 159 | 150 | 179 | 488 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 10 | 6 | 5 | 21 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 1 | 1 |
| Race (NIH/OMB): Black or African American | Participants | 18 | 13 | 19 | 50 |
| Race (NIH/OMB): White | Participants | 129 | 144 | 156 | 429 |
| Race (NIH/OMB): More than one race | Participants | 8 | 3 | 8 | 19 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 1 | 2 | 3 |
| Region of Enrollment: United States | participants | 165 | 167 | 191 | 523 |
6. Primary Endpoint
The registry lists the primary outcome as Geometric Mean Titer (GMT) Based on Vaccinia-specific Individual Peak Plaque Reduction Neutralization Titers (PRNT) Following 2 Doses of IMVAMUNE® Lyophilized Versus Following 2 Doses of IMVAMUNE® Liquid Administered Subcutaneously, ITT Population, measured over Days 14, 28 and 180 after 2nd vaccination.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | titer |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is a geometric mean titer (GMT) based on each participant’s individual peak vaccinia-specific plaque reduction neutralization titers (PRNT) after the second vaccination. Blood was tested using vaccinia-Western Reserve as the assay antigen. The registry lists assessment times as Days 14, 28 and 180 after the second vaccination.
A PRNT assay measures the ability of antibodies in a blood sample to neutralize virus under laboratory conditions. A titer represents the assay’s measure of that activity; it is not itself a clinical outcome such as prevention of illness. The registry defines the participant-level value used for the GMT as the individual peak titer after the second vaccination. Values below the assay’s limit of detection were replaced with 7.5, described as half the lower limit of detection.
A geometric mean is appropriate for measurements such as titers that can be strongly right-skewed: it summarizes values on a multiplicative scale rather than treating equal absolute increments as equivalent across the range. This is a general statistical explanation, not a statement about an unreported analysis decision. The registry reports the primary group summaries with 95% confidence intervals.
The ITT population for immunogenicity summaries includes participants with results for the visit and analyzes them according to randomized assignment. The record states that not receiving the second vaccination, or receiving it outside the window, was not considered in this population definition. The endpoint therefore summarizes measured immune-response values in the specified analysis population; it does not mean that every randomized participant contributed a result at every listed time.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary arm estimates are a GMT of 77.9 for the lyophilized subcutaneous group, with a 95% confidence interval from 62.9 to 96.5, and a GMT of 46.7 for the liquid subcutaneous group, with a 95% confidence interval from 37.9 to 57.4. The reported analysis includes 161 participants in the lyophilized group and 164 in the liquid group. These are estimates of peak vaccinia-specific PRNT titers, not direct measures of clinical protection.
The confidence intervals describe uncertainty in each group’s estimated GMT under the analysis used. They are not ranges containing a fixed proportion of individual participants’ titers, and they do not establish how much participants’ responses varied unless a measure of individual-level dispersion is also given. The registry identifies 95% confidence intervals for the arm estimates. It does not provide individual-level distributions in the registry record for this analysis.
The registry also posts a non-inferiority analysis labelled “Mean Difference (Final Values).” Its estimate is -0.74, with a 97.5% confidence interval from -1.23 to -0.25. The record does not identify the scale or method used for this comparison, and it does not give a p-value. The arm GMT summaries and this reported comparison should not be treated as interchangeable quantities: one pair gives group-level GMTs, while the other is the sponsor’s reported comparative statistic on a scale that is not specified in the registry record.
A non-inferiority conclusion depends on the prespecified margin and the interpretation of the confidence interval relative to that margin. The margin is not reported in the registry record. Consequently, the posted estimate and interval can be described, but the registry entries do not establish whether the trial met its non-inferiority criterion. The registry does not report the rationale for the margin, or the detailed analysis method underlying the estimate.
The trial also had a liquid intradermal group, but no primary estimate comparing that group with either subcutaneous group is included in the primary result. The presence of three arms does not make the primary result a three-way comparison. Separate secondary outcomes refer to GMT comparisons for the intradermal and subcutaneous groups, as well as for the two subcutaneous formulations, in ITT and per-protocol populations. Numerical results for those secondary comparisons are not reported in the registry record.
These results should be read as estimates of an immunogenicity endpoint in the stated population and follow-up schedule. They do not, by themselves, demonstrate the clinical consequences of the measured titers or settle comparisons that were not posted.
9. Statistical Methods Explained
The registry reports group-level geometric mean titers and confidence intervals, together with a sponsor-reported non-inferiority comparison. These statistics answer related but distinct questions. A group GMT describes the central value of titers on a multiplicative scale. A comparative estimate describes the contrast between groups according to a particular analysis scale and method. The registry labels the latter as a mean difference in final values, but the precise scale and method are not reported in the registry record.
What does a confidence interval express?
In general, a confidence interval expresses the uncertainty associated with an estimated quantity under the assumptions of the statistical procedure used. A narrower interval indicates greater precision for that estimate; a wider interval indicates more uncertainty. A confidence interval is not a guarantee that the underlying value lies within its limits, and it is not a description of the spread of individual observations. The posted 95% intervals accompany the two GMT estimates. The comparative non-inferiority result has a 97.5% interval. Those confidence levels belong to different reported results and should be kept attached to their own estimates.
The arm intervals are 62.9 to 96.5 for the lyophilized subcutaneous GMT and 37.9 to 57.4 for the liquid subcutaneous GMT. The interval for the sponsor’s comparative estimate is -1.23 to -0.25. Because the registry does not identify the comparative scale, the interval’s values cannot be interpreted as a contrast in raw titer units. Nor should overlap or non-overlap of separate arm confidence intervals be substituted for the reported comparative analysis: a direct contrast and its uncertainty are the relevant quantities for a group comparison.
Why use a geometric mean for titers?
As a general statistical matter, biological titers often span a range in which multiplicative changes are more meaningful than equal absolute changes. Taking logarithms converts multiplicative relationships into additive ones; an average on the transformed scale can then be expressed as a geometric mean on the original scale. This approach can make a summary less dominated by a few very large observations than an arithmetic mean would be, when the measurement distribution is right-skewed. The registry names the endpoint as a GMT, but does not report the details of the calculation or diagnostic checks for its distribution.
The registry also specifies a rule for values below the detection limit: replace them with 7.5, described as half the lower limit of detection. Such substitutions allow a numerical summary when the assay cannot quantify a value below its threshold, but they can affect estimates if many observations lie below that threshold. The frequency of below-limit values is not reported in the registry record, so the influence of the replacement rule cannot be assessed from the stated details.
What is the role of the ITT population?
In general, an intention-to-treat approach preserves participants in their randomized groups for analysis, supporting the comparison created by random assignment. Here, the registry defines the immunogenicity ITT population as participants with results for the visit, analyzed as randomized. It also states that not receiving the second vaccination or receiving it outside the window was not considered. This is not a complete accounting of every randomized participant at every assessment: the population requires an available result for the visit. The number with results may therefore differ by assessment, but visit-specific counts are not reported in the registry record.
The registry lists per-protocol secondary analyses as well, but the criteria for that population are not reported in the registry record. In general, per-protocol analyses focus on participants who met specified protocol requirements. Such analyses can be informative alongside an ITT analysis, but they may be more vulnerable to bias if exclusions are related to treatment assignment or outcomes. No conclusion about the degree of that risk can be made without the criteria and participant flow.
How should the non-inferiority result be read?
In general, a non-inferiority analysis tests whether the effect of one intervention is not worse than a comparator by more than a prespecified, clinically acceptable margin. The conclusion depends on the direction and scale of the contrast, the margin, and the confidence interval. A confidence interval that crosses the margin does not support the same conclusion as one wholly on the acceptable side. In this trial, the registry labels the result non-inferiority and gives an estimate of -0.74 with a 97.5% confidence interval from -1.23 to -0.25, but the margin, scale, direction convention and analysis method are not reported. It is therefore not possible to determine from these registry entries alone whether the criterion was met.
Sample-size calculations, when presented as planning illustrations, use assumptions about a target effect and statistical procedure. They are not observed power and do not show the probability that the trial detected an effect after the data were collected. The registry’s stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is expressed as a fraction of the observed effect. Those calculations are planning illustrations, not evidence of the trial’s original design justification. The original sample-size justification and its assumptions are not reported in the registry record.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| not stated | Mean Difference (Final Values) -0.74 | -1.23 to -0.25 | not reported |
The registry’s sponsor-reported analysis is labelled non-inferiority and gives a mean difference in final values of -0.74, with a 97.5% confidence interval from -1.23 to -0.25. No p-value, analysis method, scale or non-inferiority margin is reported in the registry record. Those omissions prevent a full reconstruction of the sponsor’s conclusion from the posted statistic alone.
The primary arm summaries are GMT 77.9 (95% confidence interval 62.9 to 96.5) for the lyophilized subcutaneous group and GMT 46.7 (95% confidence interval 37.9 to 57.4) for the liquid subcutaneous group. They are not a substitute for the sponsor’s comparative estimate, because the scale of that estimate is unspecified. The sponsor’s own analysis takes precedence over a simple unadjusted recalculation when a discrepancy is flagged; no discrepancy is flagged in the registry entries for this trial. A recalculated comparison estimate is not reported in the registry record, so no numerical recalculation can be compared with the sponsor’s estimate.
The non-inferiority label identifies the analysis type but does not, on its own, establish that a non-inferiority criterion was satisfied. The margin and the convention for the direction of the contrast are essential to that interpretation and are not reported in the registry record. The safest reading is to retain the reported estimate and interval as the sponsor’s posted result, while treating its formal conclusion as indeterminate from the available details.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists 10 outcome measures and 8 analyses. The primary endpoint is the PRNT-based GMT comparison between the two subcutaneous formulations in the ITT population. Secondary outcomes include a grade 3 and 4 laboratory toxicity measure, GMT comparisons involving the lower-dose intradermal group, and comparisons of the lyophilized and liquid subcutaneous formulations in ITT and per-protocol populations. Numerical results for all listed secondary outcomes are not reported in the registry record.
When a trial evaluates several outcomes, time points, populations or comparisons, the chance of at least one apparently notable result can increase if each result is interpreted independently. Statistical approaches that address multiplicity can control or describe that risk. This is a general statistical concern; the actual approach for this trial is not reported in the registry record. No multiplicity adjustment, hierarchy among secondary endpoints, or plan for selecting results is described in the registry record.
The primary endpoint lists Days 14, 28 and 180 after the second vaccination. The record does not specify in the registry record whether one of these visits was designated as the primary time point for formal testing, or how estimates across visits were handled. It is therefore not appropriate to infer a time-point selection rule or a correction for repeated assessments.
The ITT immunogenicity population includes participants with a result for the visit and analyzes them as randomized. The record explicitly states that not receiving the second vaccination or receiving it outside the window was not considered. This definition clarifies assignment and eligibility for the summaries, but it does not provide the number of missing results or explain why results were unavailable. Missing-data reasons, imputation beyond the below-detection substitution, and sensitivity analyses are not reported in the registry record.
Per-protocol populations are named for secondary analyses, but their criteria and sizes are not reported. The registry also does not report interim analyses, stopping rules, or a statistical analysis plan in the registry record for this analysis. These gaps limit assessment of how outcome selection, missing observations and repeated comparisons may have influenced the overall evidence.
12. 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 |
|---|---|---|---|
| Lyophilized, Subcutaneous | 1 | 165 | 0.6% |
| Liquid, Subcutaneous | 2 | 167 | 1.2% |
| Liquid, Intradermal | 1 | 191 | 0.5% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Lyophilized, Subcutaneous | 0 of 165 |
| Liquid, Subcutaneous | 0 of 167 |
| Liquid, Intradermal | 0 of 191 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Lyophilized, Subcutaneous | 164 of 165 |
| Liquid, Subcutaneous | 161 of 167 |
| Liquid, Intradermal | 191 of 191 |
Most frequent serious adverse event terms
| Event term | Organ system | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal |
|---|---|---|---|---|
| Appendicitis | Infections and infestations | 0 of 165 | 1 of 167 | 0 of 191 |
| Back pain | Musculoskeletal and connective tissue disorders | 0 of 165 | 0 of 167 | 1 of 191 |
| Colitis | Gastrointestinal disorders | 0 of 165 | 1 of 167 | 0 of 191 |
| Colitis ischaemic | Gastrointestinal disorders | 1 of 165 | 0 of 167 | 0 of 191 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Lyophilized, Subcutaneous | Liquid, Subcutaneous | Liquid, Intradermal |
|---|---|---|---|---|
| Injection site erythema | General disorders | 128 of 165 | 136 of 167 | 190 of 191 |
| Injection site pain | General disorders | 155 of 165 | 152 of 167 | 125 of 191 |
| Injection site swelling | General disorders | 108 of 165 | 116 of 167 | 190 of 191 |
| Injection site pruritus | General disorders | 82 of 165 | 81 of 167 | 170 of 191 |
| Malaise | General disorders | 90 of 165 | 83 of 167 | 98 of 191 |
| Headache | Nervous system disorders | 83 of 165 | 72 of 167 | 79 of 191 |
| Myalgia | General disorders | 81 of 165 | 69 of 167 | 58 of 191 |
| Vaccination Site Discolouration | General disorders | 16 of 165 | 7 of 167 | 122 of 191 |
| Nausea | Gastrointestinal disorders | 40 of 165 | 36 of 167 | 44 of 191 |
| Vaccination Site Nodule | General disorders | 41 of 165 | 34 of 167 | 35 of 191 |
Serious events with the highest arm-level rate: colitis ischaemic (0.6%), appendicitis (0.6%), colitis (0.6%), back pain (0.5%).
The registry lists serious adverse events and other adverse events separately for the three groups. For the lyophilized subcutaneous group, 1 of 165 participants was affected by a serious adverse event, and 164 of 165 were affected in the “other” adverse-event category. For the liquid subcutaneous group, the corresponding figures are 2 of 167 and 161 of 167. For the liquid intradermal group, they are 1 of 191 and 191 of 191. The recorded number of deaths is 0 in each group.
These counts are safety summaries, not comparisons adjusted for follow-up time or other factors. The registry entries do not define the “other” category, explain event collection or attribution, or report the duration of safety follow-up. The serious adverse-event terms listed include Colitis ischaemic at 0.6%, Appendicitis at 0.6%, Colitis at 0.6% and Back pain at 0.5%. The registry entries do not link each term to a particular treatment group or provide the term-specific denominators, so those percentages should not be assigned to a group.
Counts of affected participants do not communicate severity beyond the category labels, timing, recurrence or relationship to vaccination. The registry lists the number affected, rather than establishing that the vaccine caused each event. These figures can describe what was recorded, but the available information does not support a causal interpretation or a detailed comparison of safety between groups.
13. What the Result Does, and Does Not, Mean
The primary result is an immunogenicity comparison based on peak vaccinia-specific PRNT titers after the second vaccination. The lyophilized subcutaneous group had a posted GMT of 77.9, and the liquid subcutaneous group had a posted GMT of 46.7. Their respective 95% confidence intervals were 62.9 to 96.5 and 37.9 to 57.4. The sponsor also reported a non-inferiority comparison of -0.74, with a 97.5% confidence interval from -1.23 to -0.25.
These statistics describe antibody-related assay measurements, not observed cases of smallpox or a direct measure of clinical protection. A laboratory titer can be useful for comparing immune responses, but the relationship between a titer and clinical outcomes is not reported in the registry record. The posted findings should therefore be interpreted as estimates of the measured endpoint, rather than as proof of a clinical benefit or lack of benefit.
The sponsor’s non-inferiority label does not resolve the formal conclusion without the non-inferiority margin, contrast direction and analysis scale. Those details are not reported in the registry record. The estimate and interval can be stated as posted, but whether they satisfy a prespecified criterion cannot be established from the registry entries.
The primary comparison covers the two subcutaneous formulations. Although a lower-dose intradermal group was included, the primary result does not establish a comparison involving that group. The registry names additional secondary analyses, including intradermal comparisons and per-protocol analyses, but their numerical results are not reported in the registry record.
The safety summaries show recorded serious adverse-event counts and “other” adverse-event counts, as well as zero recorded deaths in each group. They do not establish causality, and the registry entries do not provide the detail needed to compare event timing, duration or attribution. Overall, the evidence should be understood within its stated scope: a phase 2 randomized comparison of formulations and routes, with a primary laboratory immunogenicity endpoint and incomplete reporting of several analytic details.
14. Why This Trial Matters Statistically
This trial raises several statistical issues that commonly arise when clinical studies compare formulations, doses and administration routes. The primary comparison is between lyophilized and liquid formulations at the same stated dose, both given subcutaneously. A separate group received a lower dose by the intradermal route. Because both dose and route differ for that group, a comparison involving it cannot isolate the effect of route alone without additional design or analysis details.
The outcome is a laboratory titer summarized by a geometric mean. That choice reflects the multiplicative character often found in biological measurements and makes the analysis scale important. The registry gives group GMTs and a sponsor-reported mean difference in final values, but does not state the scale used for the comparative statistic. The contrast cannot be interpreted fully without that information.
The registry labels the comparison as non-inferiority, which makes the prespecified margin central to interpretation. A numerical estimate and confidence interval are not enough to assess the non-inferiority claim in isolation. The margin, its clinical justification, and the direction convention for the contrast are not reported in the registry record. This is a practical example of why statistical labels should be read alongside the design criteria that make them interpretable.
The trial also lists several outcomes, time points and analysis populations. Multiplicity, missing visit results and the distinction between ITT and per-protocol analyses may all matter when interpreting a collection of results. The registry entries do not report the relevant adjustment or sensitivity procedures. These are not merely technical details: they determine how confidently readers can distinguish a prespecified finding from a result selected among multiple opportunities.
Finally, the distinction between immune-response measurements and clinical outcomes is important. A precise GMT estimate can characterize the assay response while leaving unanswered questions about clinical protection. The available record makes that distinction visible and illustrates why endpoint choice, analysis scale and reporting completeness all shape the conclusions that can responsibly be drawn.
15. 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.
Several trial-specific limitations arise from the information available in the registry record. The primary outcome is a PRNT-based immune-response measure, not a reported clinical outcome. The registry entries do not describe a relationship between the measured titers and prevention of smallpox, so the clinical meaning of the group estimates cannot be established from these results alone.
The sponsor-reported non-inferiority estimate is not fully interpretable because the margin, analysis scale, contrast direction and statistical method are not reported in the registry record. Although the estimate and 97.5% confidence interval are posted, these missing details prevent independent assessment of whether the non-inferiority criterion was met. The registry also does not give a p-value for that analysis.
Details needed to assess the immunogenicity summaries are also incomplete. The frequency of values below the assay detection limit is not reported, even though those values were replaced with 7.5. Visit-specific numbers of participants with results, reasons for missing results, and sensitivity analyses are not reported. The per-protocol criteria and population sizes are likewise not reported in the registry record.
The record lists 10 outcome measures and 8 analyses, but does not report a multiplicity strategy, endpoint hierarchy, interim analyses or the detailed statistical analysis plan. This limits evaluation of how repeated outcomes and time points were handled. Randomization and triple masking are stated, but operational details about allocation concealment and masking are not reported.
The safety details provide counts of affected participants, but do not describe event duration, timing, attribution or the definition of the “other” category. The listed serious adverse-event terms are not assigned to individual arms in the registry record for this analysis. These limits mean the counts should be read descriptively, not as a complete account of comparative safety.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid IMVAMUNE® (1x10^8 TCID50) Administered Subcutaneously and a Lower Dose Liquid IMVAMUNE® (2x10^7 TCID50) Administered Intradermally — NCT00914732.
- Registry record last updated 2021-02-03; status last verified 2011-01.
- Results first posted 2021-01-12.
- 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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19. Record Summary
NCT00914732 is a completed phase 2 randomized, triple-masked, parallel trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It compared lyophilized and liquid IMVAMUNE® at 1x10^8 TCID50 by subcutaneous administration and included a lower-dose liquid intradermal group. The registry reports enrollment of 523, with a recorded start of 2010-02 and primary completion in 2011-04.
The primary endpoint was the GMT of participant-level peak vaccinia-specific PRNT titers after the second vaccination, assessed on Days 14, 28 and 180. Posted estimates for the subcutaneous groups were 77.9 for the lyophilized formulation and 46.7 for the liquid formulation. The sponsor-reported non-inferiority estimate was -0.74, with a 97.5% confidence interval from -1.23 to -0.25.
The non-inferiority margin and analysis scale are not reported in the registry record. Secondary numerical results and several details about missing data, multiplicity and analysis methods are also not reported in the registry record. The findings therefore describe the posted immunogenicity estimates and safety counts, with limits on further interpretation.