Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine. (NCT02013245), a randomized phase 1 study. The primary outcome is Number of Participants With Adverse Events up to 210 Days After Vaccination.

2. Clinical Question

3. Trial Design

This was a phase I, randomized, controlled, quadruple-masked, parallel-group study of MTBVAC compared with BCG. The registered title describes a dose-escalation study, with three MTBVAC dose groups and a BCG control group. The registry lists 36 participants enrolled and 9 participants in each group: MTBVAC Group 1, MTBVAC Group 2, MTBVAC Group 3, and the BCG Control Group.

The low, middle, and high MTBVAC doses were recorded as 5 x 10E03 CFU/0.1mL, 5 x 10E04 CFU/0.1mL, and 5 x 10E05 CFU/0.1mL, respectively. The BCG dose was recorded as 5 x 10E05 CFU/0.1mL. The intervention descriptions identify both vaccines as live vaccines. Who was masked, how the dose escalation was operationalized, and how allocation was generated are not reported in the registry record.

The study started in 2013-01, reached primary completion in 2014-06, and is listed as completed. Biofabri, S.L is identified as the sponsor. The primary outcome had a 7 months follow up timeframe and is titled as a count of participants with adverse events up to 210 days after vaccination. The registry also lists one secondary outcome concerning a three-cytokine-positive CD4+ T-cell response. Detailed procedures, including the order and timing of vaccinations and the schedule of immunogenicity assessments, are 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.

Overall Study

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 Participants With Adverse Events up to 210 Days After Vaccination, measured over 7 months follow up.

The primary endpoint counts participants with adverse events up to 210 days after vaccination. The registry description frames it as a safety and reactogenicity assessment and includes solicited symptoms during the 7-day period following vaccination, unsolicited symptoms during the 210-day period, vaccine-related grade 3 local and general symptoms during the 210-day period, serious adverse events throughout the entire study period, and haematological and biochemical safety test levels before and after vaccination.

Counting affected participants is a way to describe how many people experienced at least one event within a category; it does not, by itself, describe the number of separate events each person had, their duration, or their clinical details. The registry reports 9 participants with the primary outcome in each group. It does not provide event-level descriptions, individual laboratory values, or group summaries for the laboratory tests in the record. Those omissions limit interpretation of what the counts represent beyond the endpoint definition.

Safety outcomes are used in early-phase studies to characterize observed tolerability and identify events that warrant further study. This general purpose does not mean that the endpoint alone establishes comparative safety or predicts outcomes in populations outside the enrolled volunteers. The registry also lists immunogenicity as a study purpose and identifies a secondary cellular-response outcome, but the record does not report its results in the registry record for this analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, quadruple-masked, parallel study. Randomization is intended, in general, to reduce systematic differences between groups at assignment; masking is intended to reduce the influence of knowledge of assigned treatment on care, reporting, or assessment. These are general concepts, not confirmation of the procedures used in this trial. The method for generating the sequence, allocation concealment, and the roles of the masked parties are not reported in the registry record.

What does a participant count convey?

The primary endpoint is a binary participant-level outcome: a participant either appears in the count of people with adverse events or does not. In general, binary outcomes are summarized by counts of participants with and without the event, or by an estimate comparing those proportions. Here, the registry lists 9 participants with the outcome in each group and 9 participants in each group. It does not give a comparative estimate, its confidence interval, or a p-value. The displayed counts should therefore be read descriptively, not as evidence from a hypothesis test.

Counts do not preserve all information about events. One participant may experience more than one event, and different participants may have events of different types or severity. The primary endpoint description includes multiple safety components, but the record does not supply detailed component-level data. The reported participant count cannot be used to reconstruct the frequency of individual event types or laboratory changes.

Why might a comparison be unavailable?

The record states that values were missing or not estimable for a two-arm comparison of the binary endpoint. This means a reported estimate for that comparison is not available in the record. It does not identify the particular reason beyond that statement. A statistical comparison would require a defined contrast and sufficient outcome information, along with a specified method. The comparison method and any model or adjustment are not reported in the registry record. No replacement estimate should be inferred from the group counts.

A confidence interval, as a general statistical concept, describes a range of values compatible with the observed data under a chosen method and its assumptions. Its width conveys precision: a wider interval represents greater uncertainty. No confidence interval is reported for the primary outcome comparison, so the precision of a difference or ratio between groups cannot be assessed from this record. A p-value, in general, summarizes how incompatible data are with a specified null model; it does not measure the probability that a treatment works. No p-value or null hypothesis test is reported.

How should dose groups be considered?

The study has three MTBVAC dose groups and one BCG control group. A dose-escalation design can be used, in general, to examine outcomes across increasing doses, but the registry does not describe the escalation rules, decision criteria, or dose-selection process. The observed counts are identical across the listed groups for the reported primary endpoint. The record does not provide a planned trend test or an analysis treating dose as an ordered quantity. No dose-response conclusion can be drawn from the counts alone.

The overall enrollment and the group counts describe the study size, but do not reveal how the study size was chosen. The sample-size justification and any formal power calculation for the trial are not reported in the registry record. A planning illustration based on an observed effect is not the same as the trial's original design rationale or an assessment of observed power. Planning sample sizes are hypothetical quantities that depend on assumptions; they do not add evidence about the participants who were actually enrolled.

What are the limits of the available analysis?

The registry lists no analyses. It does not report an analysis population, a statistical analysis plan, handling of missing outcome data, or model assumptions. General statistical methods for binary outcomes can account for sampling uncertainty and permit contrasts, but their validity depends on the data and the prespecified analysis. Without a reported method and an estimable comparison, the outcome counts should remain descriptive. No adjusted or unadjusted effect estimate should be attributed to this study.

The sample-size illustration's stated assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. These assumptions describe a planning illustration, not a reported protocol analysis. They do not indicate that the trial was designed with those assumptions, and they do not turn the observed counts into an inferential result. No numeric planning result is reported in the registry entries available for this analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("MTBVAC Group 1", "MTBVAC Group 2", "MTBVAC Group 3", "BCG Control Group")
n      <- c(9, 9, 9, 9)
events <- c(9, 9, 9, 9)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  MTBVAC Group 1  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7
ARM  MTBVAC Group 2  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7
ARM  MTBVAC Group 3  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7
ARM  BCG Control Group  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one secondary outcome: the number of participants with a three-cytokine-positive CD4+ T-cell response. The primary safety endpoint and this secondary endpoint address different outcomes. The record does not report results for the secondary outcome in the registry record, nor does it describe a multiplicity strategy for evaluating multiple outcomes or comparisons. Without a reported strategy, it is not possible to determine whether any inferential results would have been adjusted for repeated testing. No analysis is listed.

Missing-data handling is not reported in the registry record. The posted group sizes and outcome counts do not explain whether any enrolled participants were excluded from an analysis, whether all randomized participants were followed for the full timeframe, or how incomplete symptom or laboratory records were handled. The record does not state whether the analysis followed intention-to-treat, per-protocol, safety, or another population definition. The number of analyzed participants is therefore not separately established beyond the listed group counts.

In general, missing outcomes can affect interpretation when the probability of missingness relates to a participant's condition or outcome. Statistical approaches depend on why data are missing and on assumptions that should be made explicit. No such assumptions or sensitivity analyses are reported. The record also does not provide a detailed statistical analysis plan, prespecified contrasts, covariate adjustment, interim-analysis procedures, or stopping rules. Their status is not reported in the registry record, and none should be inferred from the phase or design description alone.

12. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious-adverse-event figures are participant counts: 0 affected participants among 9 at risk in each group. This is a report of zero participants recorded with a serious adverse event in the registry's grouping; it is not evidence that the underlying risk is exactly zero. The registry does not provide serious-event descriptions, dates, duration, relatedness assessments, or additional follow-up detail for these figures. It also does not report death counts, so those should not be read as zero.

For the other-adverse-event category, the record reports 9 affected participants among 9 at risk in every group. That category is not described in enough detail to identify the events, their severity, or whether they were considered vaccine-related. The primary endpoint description separately mentions solicited and unsolicited symptoms and grade 3 vaccine-related symptoms, but the available counts do not break out those components. The registry reports a 7-day solicited-symptom period, a 210-day unsolicited-symptom period, and serious adverse events throughout the entire study period.

In general, adverse-event counts are descriptive and should be interpreted in light of how events were defined and collected. The registry does not provide participant-level narratives or event-level totals, so the figures cannot characterize the full safety profile.

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

The posted results permit a limited description: all four groups have 9 participants listed, and the registry reports 9 participants with the primary adverse-event outcome in each group. It also reports no serious adverse-event-affected participants in each group, while the other-adverse-event category lists 9 affected participants in each. These figures are counts, not estimates of a comparative treatment effect.

The data do not show whether the groups differ in specific adverse events, event severity, timing, or laboratory changes. No confidence intervals, p-values, or comparative estimates are reported, and the registry says values for a two-arm comparison of the binary endpoint were missing or not estimable. The absence of an inferential comparison is not proof of equivalence. Similarly, matching observed counts do not establish that the vaccines have matching safety outcomes beyond this recorded endpoint and these participants.

The study was designed to evaluate safety and immunogenicity, but the registry entries available do not include results for the listed secondary cellular-response outcome. The record therefore does not support an interpretation of comparative immunogenicity. It also does not establish effects in populations other than the volunteers described by the official title, or outcomes beyond the reported follow-up and measures.

In general, a phase I study can provide early descriptive evidence and inform questions for further evaluation, but conclusions depend on the outcomes collected, the number of participants, completeness of follow-up, and analysis methods. Here, the registry does not report a statistical analysis plan or analysis population. The careful conclusion is confined to the counts reported and the uncertainty created by missing comparative analyses and limited event detail. No treatment recommendation follows from these registry figures.

14. Why This Trial Matters Statistically

This trial is statistically notable for its four-group dose-escalation structure: three MTBVAC doses were compared with a BCG control group, with 9 participants listed in each group. That structure raises questions about both the comparison with control and patterns across doses. The registry reports no analysis that addresses either question. A design description alone does not establish how those comparisons were to be performed.

The primary outcome is a participant count, while the endpoint description combines multiple safety elements and timeframes. This illustrates a general statistical distinction: a single summary count can be easy to communicate but may conceal variation in event type, severity, and timing. Without component-level results, readers cannot assess whether the same kinds of events underlie equal counts in different groups.

The record also distinguishes between observed counts and comparative inference. Identical counts across groups do not provide a confidence interval or demonstrate equivalence, and the registry explicitly notes that a two-arm comparison was not estimable. Stating that limitation matters: it prevents descriptive outcome counts from being mistaken for a formal test or a precise estimate.

Finally, the listed secondary outcome shows that the trial's aims extended beyond safety, but its results are not reported in the registry entries. Statistical interpretation must follow the outcomes actually reported rather than assume that all stated aims have corresponding results. Together, the trial highlights the importance of reporting outcome definitions, analysis populations, missing-data handling, and the methods for comparing multiple dose groups.

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.

The registry entries give only aggregate participant counts for the primary outcome and adverse-event categories. They do not identify particular symptoms, event narratives, laboratory values, or the number of individual events. Although the endpoint description names several safety components, separate results for solicited symptoms, unsolicited symptoms, grade 3 vaccine-related symptoms, and haematological and biochemical tests are not reported in the registry record.

The record says a two-arm comparison of the binary endpoint was missing or not estimable and lists no analyses. It does not give an effect estimate, confidence interval, p-value, model, or prespecified comparison method. Consequently, comparative precision cannot be evaluated. The record also does not explain why the comparison was unavailable.

Further trial-specific details that would help interpretation are not reported in the registry record: allocation-generation procedures, masking roles, escalation rules, analysis populations, missing-data handling, and the sample-size justification. There is no reported result for the listed secondary immunogenicity outcome in the registry record. Death counts are not reported. The study's recruitment and outcome reporting also do not establish whether every participant had complete follow-up across the stated periods.

These limitations do not invalidate the descriptive counts, but they constrain what those counts can establish. In particular, they do not support a precise comparison between vaccines, a dose-response inference, or conclusions about immune response. The small group size and missing inferential analysis make cautious, outcome-specific interpretation essential.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose-Escalation Study to Evaluate the Safety and Immunogenicity of MTBVAC Vaccine in Comparison With BCG Vaccine. — NCT02013245.
• Registry record last updated 2017-03-24; status last verified 2017-02.
• Results first posted 2017-03-24.
• 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.

19. Record Summary

NCT02013245 is a completed phase I randomized, quadruple-masked, parallel dose-escalation study sponsored by Biofabri, S.L. The registry lists 36 enrolled participants, with 9 assigned to each of three MTBVAC dose groups and the BCG control group. The study started in 2013-01 and reached primary completion in 2014-06.

The primary outcome counted participants with adverse events up to 210 days after vaccination. The registry reports 9 participants with this outcome in each group, 0 participants with serious adverse events in each group, and 9 participants with other adverse events in each group. One secondary outcome concerns a three-cytokine-positive CD4+ T-cell response; its result is not reported in the registry record for this analysis. No analyses are listed, and a two-arm comparison of the binary endpoint is described as missing or not estimable. The record does not support a comparative statistical conclusion.