Evaluation of Immune Memory to Twinrix or Comparator by Challenge Dose Administration 4 Years After Primary Vaccination: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Immune Memory to Twinrix or Comparator by Challenge Dose Administration 4 Years After Primary Vaccination (NCT00684671), a randomized phase 4 study. The primary outcome is Number of Subjects With Anamnestic Response to the Challenge Dose for Anti-hepatitis A (Anti-HAV) Antibodies.

2. Clinical Question

3. Trial Design

This was a completed, Phase 4, randomized, parallel-group trial with no masking. The registry lists 506 participants enrolled. The study evaluated a challenge dose administered 4 years after primary vaccination; only people who participated in the primary study were invited to the extension and challenge-dose phase.

Participants were assigned to one of three challenge-dose groups. The Twinrix group received a single dose of combined hepatitis A and hepatitis B vaccine. The Engerix + Havrix group received separate hepatitis B and hepatitis A vaccines, and the HB VAX PRO + Vaqta group also received separate hepatitis B and hepatitis A vaccines. The registry does not report the method used to generate or conceal the random allocation sequence.

The primary immunogenicity analysis was conducted in the According-to-Protocol cohort. For the primary endpoint, the registry lists 167 participants in the Twinrix group, 168 in the Engerix + Havrix group, and 163 in the HB VAX PRO + Vaqta group. These are endpoint denominators, not a restatement of total enrollment.

The primary endpoint was anamnestic anti-hepatitis A antibody response one month after the challenge dose. Secondary outcomes named in the registry include antibody concentrations, solicited and unsolicited symptoms, and serious adverse events. Detailed results are posted for unsolicited symptoms; results for the other named secondary outcomes are not reported in the registry record. Details of the original vaccination protocol, the trial’s original sample-size justification, and the statistical analysis plan 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on the According-to-Protocol (ATP) cohort for analysis of immunogenicity.

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 Anamnestic Response to the Challenge Dose for Anti-hepatitis A (Anti-HAV) Antibodies, measured over One month after the challenge dose..

The primary endpoint counted participants with an anamnestic response in anti-hepatitis A antibodies one month after the challenge dose. An anamnestic response is a rise in antibody response after a later exposure, interpreted in relation to the participant’s antibody status and concentration before the challenge dose.

The registry defines the response differently for initially seronegative and initially seropositive participants. For initially seronegative participants, the post-challenge concentration had to reach the stated cutoff of 15 mIU/mL. For initially seropositive participants with a pre-vaccination concentration below 100 mIU/mL, the post-challenge concentration had to be at least four times the pre-vaccination concentration. For those with a pre-vaccination concentration of 100 mIU/mL or higher, it had to be at least two times the pre-vaccination concentration.

This endpoint is used to describe an antibody response following the challenge dose. It is a participant count rather than a continuous antibody concentration, and it does not directly measure clinical disease, transmission, or duration of protection. Its interpretation also depends on the registry’s response definition and the ATP immunogenicity population. Results for anti-hepatitis B antibodies are listed among the secondary outcomes, but their detailed results are not reported in the registry record.

7. Results Posted in the Registry

• Engerix + Havrix Group: 97.6% (164/168) versus 98.2% (164/167) on control; risk difference -0.6 percentage points (95% CI -3.6 to 2.5), risk ratio 0.99 (0.96–1.03); unadjusted two-proportion z-test p = 0.708.
• HB VAX PRO + Vaqta Group: 99.4% (162/163) versus 98.2% (164/167) on control; risk difference 1.2 percentage points (95% CI -1.2 to 3.5), risk ratio 1.01 (0.99–1.04); unadjusted two-proportion z-test p = 0.326.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Subjects Reporting Unsolicited Symptoms

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Engerix + Havrix Group: 5.9% (10/170) versus 16.3% (28/172) on control; risk difference -10.4 percentage points (95% CI -17.0 to -3.8), risk ratio 0.36 (0.18–0.72); unadjusted two-proportion z-test p = 0.002.
  • HB VAX PRO + Vaqta Group: 12.8% (21/164) versus 16.3% (28/172) on control; risk difference -3.5 percentage points (95% CI -11.0 to 4.0), risk ratio 0.79 (0.47–1.33); unadjusted two-proportion z-test p = 0.367.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Engerix + Havrix Group than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between HB VAX PRO + Vaqta Group and the control. The interval gives the range of effects that remain compatible with the data.

The registry names secondary outcomes covering anti-hepatitis A and anti-hepatitis B antibody concentrations, solicited and unsolicited symptoms, and serious adverse events. Detailed numerical results and comparisons are posted for unsolicited symptoms. Detailed results for the other named secondary outcomes are not reported in the registry record, so an overall numerical pattern across all secondary endpoints cannot be established from the posted results.

The primary outcome concerns an antibody response to the challenge dose; unsolicited symptoms concern reported events during the 31-day follow-up period. They address different aspects of the study and should not be treated as corroborating measures of the same effect. The unsolicited-symptom comparisons do not alter the interpretation of the primary immunogenicity endpoint.

Unadjusted secondary comparisons carry less weight when multiple outcomes or contrasts are examined. Each additional comparison creates another opportunity for an apparently notable result to arise by chance, while the registry does not report a multiplicity adjustment or a hierarchy for interpreting secondary endpoints. The unadjusted p-values should therefore be considered alongside the estimates, confidence intervals, definitions, and follow-up period, rather than as stand-alone evidence.

The registry does not report whether these secondary outcomes were prespecified in a detailed analysis plan, how missing observations were treated, or whether all planned analyses are represented in the record. Without that information, the secondary findings are best understood as descriptive and exploratory. They can identify patterns for further evaluation, but do not provide the same focused evidence as a clearly specified primary endpoint with a complete analysis plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Anti-hepatitis A (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations
• Anti-hepatitis A (Anti-HAV) and Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Concentrations
• Number of Subjects Reporting Solicited Symptoms
• Number of Subjects Reporting Unsolicited Symptoms
• Number of Subjects With Serious Adverse Events (SAEs) Since the Last Study Visit of the HAB-160 (NCT00603252) Long-term Follow-up Study Considered by the Investigator to Have a Causal Relationship to Primary Vaccination
• Number of Subjects Reporting Serious Adverse Events (SAEs)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the registry’s anamnestic response definition or did not. The displayed counts therefore describe participants with the event among those analyzed. The endpoint is not an average antibody concentration, and its dichotomous definition discards information about how far an individual’s concentration was above or below the response threshold.

What does a risk difference express?

A risk difference compares the proportion with the event in one group with the proportion in the reference group. A value of zero corresponds to equal observed proportions. A negative estimate means the event proportion in the named comparison group is lower than in the Twinrix group; a positive estimate means it is higher. The posted primary risk differences are -0.006 for Engerix + Havrix and 0.012 for HB VAX PRO + Vaqta, each compared with Twinrix.

Risk differences are expressed on the probability scale, so they describe an absolute contrast rather than a relative contrast. Relative risk and odds ratio estimates are also listed for the primary comparisons, but those measures answer a different question: relative risk compares event proportions as a ratio, while an odds ratio compares event odds. When the event is common, odds and probabilities are not interchangeable. The posted relative measures have intervals that are broad, so they should not be read as precise estimates of a relative effect.

How should confidence intervals be read?

A confidence interval expresses uncertainty around an estimated contrast under the statistical procedure used. It gives a range of values reasonably compatible with the observed data and method, rather than a guarantee that the true value lies within its limits. For the primary risk differences, both intervals include zero. That means the posted intervals are compatible with a zero contrast and with contrasts on either side of zero. The interval limits also show why the estimates should not be interpreted solely from their point values.

What does the p-value add?

A p-value summarizes how unusual data at least as incompatible with a specified null hypothesis would be if that null model were correct. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a difference. The posted primary p-values are unadjusted. The registry does not report the exact test used to obtain them, the confidence-interval construction method, or a full analysis specification; those methods are not reported in the registry record.

For the primary comparisons, the p-values are 0.708 and 0.326. Neither provides strong evidence against a no-difference null under an unadjusted reading. That is not the same as proving identical response proportions. Precision depends on the interval widths and the amount of information in the analyzed groups, not on a p-value alone.

Why does the analysis population matter?

The primary endpoint is reported for the According-to-Protocol cohort for immunogenicity. Such an analysis population is defined by protocol-related criteria, but the exact criteria and the number excluded from any broader population are not reported in the registry record. The analysis denominators are 167, 168, and 163 across the three arms. The registry’s total enrollment is 506, and those figures should not be conflated: they describe different quantities.

Randomization is intended to support comparable groups, but interpretation also depends on how randomization was implemented, how post-randomization exclusions were handled, and whether missing outcomes were addressed appropriately. The allocation method, exclusions, missing-data method, and sensitivity analyses are not reported in the registry record. Without those details, the posted results can be described, but the robustness of the ATP estimate to those choices cannot be fully assessed.

What can be concluded from the posted comparisons?

The posted estimates describe group contrasts in the measured antibody response at the stated assessment time. They do not, by themselves, establish equivalence, non-inferiority, or clinical protection. Those conclusions require a prespecified framework and supporting design details, which are not reported in the registry record. The secondary symptom comparisons are also unadjusted, and no multiplicity procedure is reported. Accordingly, an isolated secondary p-value should carry less weight than a prespecified primary analysis interpreted with its interval and analysis population.

General statistical principle: a high event proportion in all groups can leave relatively few participants without the event, which may limit how precisely differences between groups can be estimated. The confidence intervals, rather than the apparent similarity of the observed counts alone, are the direct guide to uncertainty in these contrasts.

11. Confidence Intervals and Precision

The primary risk-difference intervals are the main guide to precision. For Engerix + Havrix compared with Twinrix, the estimate is -0.006 and the 95% confidence interval extends from -0.036 to 0.025. For HB VAX PRO + Vaqta compared with Twinrix, the estimate is 0.012 and the 95% confidence interval extends from -0.012 to 0.035. Each interval crosses zero and includes values on both sides of it.

In general, a confidence interval describes uncertainty in an estimate under the model and method used. The interval does not assign a probability to each possible true effect, and its limits are not the most extreme effects that could occur. Here, the intervals allow the possibility of no difference while also allowing differences in either direction. They therefore do not support a precise claim that the response proportions are identical, nor do they establish a directional advantage.

The width of an interval reflects both the amount of information and the variability in the data under the analysis. The endpoint denominators are 167, 168, and 163, and the event counts are high in each arm. General statistical principle: when nearly all participants meet a binary endpoint, relatively few non-events may make small between-group contrasts difficult to estimate precisely. The registry does not report a target precision or a clinical threshold for interpreting these differences.

The relative-risk and odds-ratio intervals are also posted, but their scales differ from the absolute risk-difference scale. They should be interpreted according to their own measure and interval, not treated as interchangeable summaries. The registry does not report the confidence-interval construction method, so the exact procedure behind the intervals is not reported in the registry record.

12. 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 figures are participants per arm, not total participants, for the binary outcomes in this trial. The posted planning 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 as the stated fraction of the observed effect. The trial’s own original sample-size justification and design assumptions are not reported in the registry record.

The 80% power column describes an illustrative design that, under its assumptions, would have an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column uses a higher target chance of detecting the same specified effect. These are design-planning quantities, not guarantees about a future study’s result. The listed sample sizes are calculated separately for each comparison and each stated effect fraction.

Rows planning for a smaller fraction of the observed effect require more participants per arm than rows planning for the full observed effect. This is the usual relationship: smaller effects are harder to distinguish from sampling variation, so more information is needed to detect them at a chosen significance level and power target. Planning based on an observed effect can be especially uncertain when the observed contrast is imprecise; the illustration should not be read as a firm recruitment recommendation.

These figures are sample-size planning illustrations, not observed power. Observed power is not an appropriate substitute for interpreting the estimated effect and its confidence interval. The registry does not report additional planning inputs, such as a separate target effect based on clinical importance or a missing-data allowance.

13. 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 = 0.982; treatment proportion p₁ = 0.976; average p̄ = 0.979.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2022 = 0.3964.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2022 = 0.1702.
4. n = (0.3964 + 0.1702)² / (-0.0058)² = 9,394.0, rounded up to 9,395 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 <- 0.982035928143713                          # control proportion
p1 <- 0.976190476190476                          # 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(684671)
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 = 9,395 (80% power), 12,576 (90% power)
 75% of observed effect: n per arm = 16,130 (80% power), 21,592 (90% power)
 50% of observed effect: n per arm = 35,003 (80% power), 46,858 (90% power)
power.prop.test: 9394 
Simulated power at n = 9,395 per arm: 0.804 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists multiple secondary outcomes, but a detailed statistical analysis plan is not reported in the registry record. It does not report a family-wise error strategy, a false-discovery approach, a testing hierarchy, or another method for controlling multiplicity. The posted p-values should therefore be read as unadjusted, and secondary findings should be treated cautiously when considering the number of outcomes and contrasts.

Details of missing-data handling are not reported in the registry record. The primary endpoint is analyzed in the ATP cohort for immunogenicity, but the exact ATP criteria, the number excluded from other populations, the reasons for exclusions, and the handling of participants without a recorded endpoint are not reported. No imputation method or sensitivity analysis for missing outcomes is reported. The posted arm denominators describe the analyzed participants and do not, by themselves, explain any difference between enrollment and endpoint counts.

The registry does not report an intention-to-treat analysis for the primary endpoint or a comparison of results across analysis populations. It also does not report interim analyses, stopping rules, or the trial’s original sample-size justification. These missing design and analysis details limit assessment of whether the reported analyses follow a prespecified plan and how sensitive the findings may be to exclusions or missing observations.

Randomized allocation is stated, but sequence generation and allocation concealment are not reported in the registry record. Masking is listed as none. These features matter when considering potential sources of bias, but the available record does not provide enough detail to assess their implementation. The absence of reporting should not be mistaken for evidence that a particular procedure was or was not used.

15. 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: arterial occlusive disease (0.6%), intervertebral disc protrusion (0.6%), nephritis interstitial (0.6%).

The registry lists serious adverse event counts for the three groups: 1 participant among 172 at risk in the Twinrix group, 2 among 170 in the Engerix + Havrix group, and 0 among 164 in the HB VAX PRO + Vaqta group. These are descriptive counts with their listed at-risk denominators. They do not, on their own, establish whether an event was caused by a challenge dose or whether the groups differ in safety.

The registry also lists arterial occlusive disease, intervertebral disc protrusion, and nephritis interstitial as top serious-event terms, each at 0.6%. These terms should be read as the registry’s listed serious-event terms, not as evidence that a vaccine caused them. Death counts are not reported in the registry record.

Other reported adverse-event counts are 76 of 172, 57 of 170, and 75 of 164 across the three groups, respectively. The registry’s adverse-event fields do not supply further detail about event severity, duration, recurrence, or attribution beyond the listed categories. These counts are not a substitute for a full safety assessment, and the registry does not report a formal comparative safety analysis.

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

The primary findings describe the proportion of analyzed participants who met the registry’s anamnestic anti-hepatitis A response definition one month after a challenge dose. The posted response counts are high in all three groups. The risk-difference estimates are close to zero, while their confidence intervals include zero and allow contrasts in either direction. The data therefore do not establish a clear difference between the challenge-dose groups, but they also do not establish equivalence.

The endpoint is an antibody-response measure. It does not directly measure hepatitis A disease, clinical protection, transmission, or how long an antibody response persists. The registry also lists anti-hepatitis B antibody outcomes, but detailed results for those measures are not reported in the registry record. Conclusions should stay within the endpoint and follow-up information that are posted.

The trial involved people who had participated in the primary study and were invited into an extension and challenge-dose phase. The primary immunogenicity results apply to the ATP cohort. The record does not report enough information about eligibility details, exclusions, missing data, or the original vaccination assignments to establish how broadly these results apply beyond the analyzed participants.

Unsolicited symptoms and serious adverse events provide different kinds of information from the primary antibody endpoint. Their counts can describe what was recorded during the stated assessment periods, but they do not prove causation. The secondary outcome analyses are unadjusted, and detailed results are absent for several named outcomes. No medical or clinical recommendation follows from these registry data alone.

17. Why This Trial Matters Statistically

This trial illustrates the distinction between an observed response proportion and a comparative treatment effect. All three groups have high primary response counts, but the scientific question is about the difference between groups, for which the risk differences and their confidence intervals are more informative than the counts viewed in isolation.

It also demonstrates why uncertainty matters when estimates are small. Both primary confidence intervals include zero and extend to values on either side, so a modest point estimate should not be interpreted as proof of no difference or as proof of a particular direction. A non-significant unadjusted p-value cannot establish equivalence without an appropriate prespecified design and margin.

The design focuses on immune memory after a challenge dose several years after primary vaccination, and the response definition depends on participants’ initial serostatus and pre-vaccination antibody concentration. That makes the endpoint a threshold-based immunogenicity outcome rather than a direct clinical endpoint. Distinguishing these kinds of outcomes is essential when interpreting what a trial can answer.

Finally, the record shows how incomplete reporting can constrain statistical interpretation. The ATP population is identified, but the details of exclusions, missing-data handling, multiplicity control, and the original sample-size plan are not reported in the registry record. These gaps do not erase the posted results, but they limit conclusions about robustness, precision targets, and the role of secondary findings.

18. 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 study population was drawn from participants in a primary vaccination study and invited to an extension and challenge-dose phase. This selection limits direct generalization to people who were not part of that earlier study. The detailed eligibility criteria and the composition of the invited population are not reported in the registry record.

The primary analysis used the ATP immunogenicity cohort, but the registry does not report its full definition, reasons for exclusion, or how participants with missing antibody measurements were handled. The group denominators for the endpoint are not identical, and the record does not explain whether those differences reflect missing outcomes, eligibility, or other analysis criteria. No sensitivity analysis is reported.

The endpoint is a threshold-defined antibody response assessed one month after the challenge dose. It does not report clinical illness or long-term persistence of the response. The detailed results for anti-hepatitis B antibody concentrations and other named secondary outcomes are not reported in the registry record, limiting the ability to evaluate the full range of planned immunogenicity and safety questions.

The trial is randomized and unmasked, but the sequence-generation and allocation-concealment procedures are not reported. The registry also does not report the original sample-size justification, a full statistical analysis plan, or a multiplicity strategy. Consequently, the posted unadjusted secondary comparisons and the planning illustrations cannot establish that the original study was designed around the effects now observed. These reporting limitations constrain interpretation without changing the numerical results that are posted.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Evaluation of Immune Memory to Twinrix or Comparator by Challenge Dose Administration 4 Years After Primary Vaccination — NCT00684671.
• Registry record last updated 2018-08-17; status last verified 2017-03.
• Results first posted 2009-12-03.
• 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.

22. Record Summary

This completed Phase 4 randomized, parallel-group trial evaluated a challenge dose 4 years after primary vaccination among participants invited from the primary study. The three groups received Twinrix, Engerix with Havrix, or HB VAX PRO with Vaqta. The primary endpoint counted participants with an anamnestic anti-hepatitis A response one month after challenge, using the ATP immunogenicity cohort.

Response counts were 164 of 167, 164 of 168, and 162 of 163, respectively. Both posted risk-difference confidence intervals include zero. The registry names several secondary outcomes but provides detailed comparison results for unsolicited symptoms; detailed results for other named secondary outcomes are not reported in the registry record. Key analysis-plan details, including missing-data handling and multiplicity control, are also not reported in the registry record.