DU-176b Phase 2 Dose Finding Study in Subjects With Non-valvular Atrial Fibrillation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for DU-176b Phase 2 Dose Finding Study in Subjects With Non-valvular Atrial Fibrillation (NCT00806624), a randomized phase 2 study. The primary outcome is Incidence of All Bleeding.

2. Clinical Question

The registry describes a randomized, parallel-group Phase 2 study of DU-176b in subjects with non-valvular atrial fibrillation. The central statistical question is about the incidence of all bleeding, not just major bleeding. The endpoint combines major, clinically relevant non-major, and minor events, so the reported percentages concern subjects with bleeding in any of those categories.

The three arms were DU176b 30mg, DU-176b 60 mg, and Warfarin Potassium. The study summary describes warfarin as open-label and DU-176b as double-blind. The primary comparisons reported by the sponsor cover each pair of arms. The registry record does not report a sponsor p-value for these comparisons, and it does not specify the method used for the sponsor’s comparison estimates.

The record gives a primary endpoint timeframe of 6 months while the brief summary describes 12 weeks of DU-176b administration. These are distinct registry statements; the record does not clarify their relationship. The statistical interpretation therefore concerns the endpoint as recorded, rather than assuming a particular follow-up schedule beyond those descriptions.

3. Trial Design

This was a randomized, parallel-group, multicenter, multinational Phase 2 study, with enrollment recorded as 234. The registry lists three arms: DU176b 30mg, DU-176b 60 mg, and Warfarin Potassium. The official title describes evaluation of safety and efficacy of two fixed dosages of DU-176b in subjects with non-valvular atrial fibrillation.

The stated eligibility description covers male and female subjects aged 18 to 80 years, inclusive, with non-valvular atrial fibrillation and a CHADS2 Score of at least 1. Subjects were to be treated on an outpatient basis. Random allocation was used. The masking classification is listed as quadruple, while the brief summary specifically describes the warfarin arm as open-label and the DU-176b dosages as double-blind. The registry record does not explain the roles included in the quadruple-masking label.

DU-176b was administered orally at two fixed doses for 12 weeks, according to the brief summary. Warfarin was the active control; investigators managed and monitored its dosing and adjusted the dose to achieve an INR of 2.0 to 3.0, inclusive. The primary endpoint is incidence of all bleeding, incorporating major, clinically relevant non-major, and minor bleeding. Its recorded timeframe is 6 months.

The primary endpoint population was not simply described as everyone enrolled. The Safety Analysis Set included subjects who received at least one dose of study drug and had at least one post-dose safety assessment. The endpoint was analyzed for subjects in that set who proceeded to the treatment period. The registry record gives arm-specific safety denominators for the posted bleeding results, but does not report the full flow of subjects from enrollment into each analysis population.

Other listed outcomes concerned major adverse cardiovascular events, biomarkers of thrombus formation, plasma concentration of DU-176, pharmacodynamic biomarkers, and clinical and laboratory safety data. The registry record does not provide enough detail to reconstruct how these secondary outcomes were analyzed or how they were prioritized relative to one another.

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: The Safety Analysis Set was defined as all subjects who received at least one dose of study drug and had at least one post-dose safety assessment. The primary endpoint were analyzed for the subjects who proceeded to the treatment period in the Safety Analysis Set.

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 Incidence of All Bleeding, measured over 6 months.

The primary endpoint is the incidence of all bleeding, expressed as the percentage of subjects with bleeds. It includes major bleeding, clinically relevant non-major bleeding, and minor bleeding. This broad endpoint counts bleeding events across the listed severity categories rather than restricting the outcome to the most severe category.

Using a percentage of participants with an event is a way to describe how frequently the outcome occurred in each treatment group. It gives a group-level summary that can be compared across the two DU-176b doses and the warfarin control. A confidence interval accompanies each arm percentage to express the uncertainty around the estimated incidence. It helps distinguish a point estimate from the range of values that remain compatible with the data under the interval’s statistical assumptions.

From a general statistical perspective, including several categories of bleeding can make the endpoint more inclusive than a major-bleeding-only measure. At the same time, the combined result does not reveal how much each category contributes. The registry record gives the combined all-bleeding outcome as the primary endpoint; the posted primary results do not separately show the incidence for major, clinically relevant non-major, and minor bleeding.

The population definition matters to interpretation. The endpoint analysis was for the Safety Analysis Set subjects who proceeded to the treatment period, with the set defined by receipt of at least one dose and at least one post-dose safety assessment. The registry lists the endpoint timeframe as 6 months, while the brief summary describes DU-176b administration for 12 weeks. The record does not clarify the relationship between these timing statements.

7. Results Posted in the Registry

• DU-176b 60 mg: 23.8% (19/80) versus 20.3% (16/79) on control; risk difference 3.5 percentage points (95% CI -9.4 to 16.4), risk ratio 1.17 (0.65–2.11); unadjusted two-proportion z-test p = 0.595.
• Warfarin Potassium: 29.3% (22/75) versus 20.3% (16/79) on control; risk difference 9.1 percentage points (95% CI -4.5 to 22.7), risk ratio 1.45 (0.83–2.54); unadjusted two-proportion z-test p = 0.191.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a subject either had an all-bleeding event during the endpoint period or did not, as captured in the posted summary. The arm results are reported as percentages, with a 95% confidence interval for each. This is a natural descriptive format when the outcome is the proportion of participants experiencing an event.

What does an arm percentage describe?

An arm percentage estimates the proportion of participants in that group who had the event. It is not a measure of the total number of bleeding episodes, because a participant-level percentage does not convey how many repeated episodes an individual may have had. The primary outcome also combines major, clinically relevant non-major, and minor bleeding, so the overall percentage does not show the category-specific pattern.

The registry lists the arm denominators as 79.0 for DU176b 30mg, 80.0 for DU-176b 60 mg, and 75.0 for Warfarin Potassium. The outcome estimates are based on the Safety Analysis Set definition and the subjects who proceeded to the treatment period. Those denominators should not be confused with the total enrollment recorded for the trial. The registry does not provide a complete account of exclusions, missing assessments, or movement between study stages.

What does a confidence interval convey?

A confidence interval gives a range of estimates compatible with the observed data under the method used to calculate it. In repeated applications of a method with the same assumptions, intervals constructed at a stated confidence level have a long-run coverage interpretation. That general explanation does not make the interval a probability statement about a particular fixed treatment effect. The reported intervals for the arm percentages describe uncertainty around those percentages; the intervals for differences describe uncertainty around the contrasts.

A difference in percentages is expressed in percentage points. The sign depends on the order in which groups are contrasted. The sponsor’s reported values are negative for the listed comparisons of DU176b 30mg against DU-176b 60 mg, DU176b 30mg against Warfarin Potassium, and DU-176b 60 mg against Warfarin Potassium. Their confidence intervals each include zero. This indicates that the posted estimates do not sharply distinguish a difference from no difference under the intervals’ assumptions; it does not prove the groups are identical.

How do the re-calculations fit?

The additional pairwise estimates are simple unadjusted re-calculations from the posted summary statistics. “Unadjusted” means they are not presented as estimates controlled for other covariates or for multiple comparisons. The registry does not report the method used for the sponsor’s own pairwise estimates, so methodological equivalence between the sponsor results and the re-calculations cannot be assumed. The re-calculated p-values are 0.595 for the DU-176b 60 mg comparison with DU176b 30mg and 0.191 for the Warfarin Potassium comparison with DU176b 30mg. The registry sponsor analyses do not include p-values for their comparisons.

In general, a p-value measures how surprising data at least as incompatible with a null hypothesis would be under a specified statistical model if that null hypothesis were true. It is not the probability that the null hypothesis is true, nor is it a measure of clinical importance. These p-values are unadjusted and do not address multiplicity across all comparisons. The registry record does not report whether the trial’s own analysis used a prespecified testing strategy or an adjustment for multiple comparisons.

Why can percentages and comparisons tell different things?

Arm percentages are descriptive estimates for individual groups. A difference estimate directly describes the contrast between two groups and has its own uncertainty. The uncertainty in a difference depends on the information in both groups and on the method used to construct the interval. Therefore, a reader should not infer the precision of a contrast solely from how close the two arm percentages appear.

More generally, event proportions can be affected by small numbers of observed events, particularly when an outcome is not common. Confidence intervals help make that uncertainty visible. The registry’s arm intervals are broad enough that the posted point estimates should not be interpreted as exact values for the underlying event incidence.

What analysis details are unavailable?

The registry record does not report the statistical method used for the sponsor’s difference estimates, whether the intervals were adjusted, how missing outcome data were handled, or whether any covariate adjustment was applied. It also does not report an analysis plan that would clarify the role of the comparisons. Those omissions limit the extent to which the calculations can be independently reproduced or compared method-for-method. The endpoint population is defined, but further detail about analysis populations and departures from that definition is not reported in the registry record.

10. Confidence Intervals and Precision

The arm-level 95% confidence intervals are 12.9% to 30.4% for DU176b 30mg, 15.8% to 34.1% for DU-176b 60 mg, and 20.2% to 40.4% for Warfarin Potassium. Their widths indicate that the estimated bleeding percentages are not highly precise. The point estimates—20.3%, 23.8%, and 29.3%—are useful summaries, but the intervals show substantial uncertainty around each.

The sponsor-reported difference intervals are also broad: -16.2 to 9.4 percentage points for DU176b 30mg compared with DU-176b 60 mg; -22.4 to 4.5 for DU176b 30mg compared with Warfarin Potassium; and -19.3 to 8.2 for DU-176b 60 mg compared with Warfarin Potassium. Each interval includes zero and allows for differences in either direction. Thus, the posted comparisons do not pin down the size or direction of a group difference with high precision.

In general, confidence intervals reflect both the observed data and the assumptions of the calculation method. They are not guarantees that the true value lies within a particular interval. The sponsor’s method for these intervals is not reported in the registry record, which limits assessment of their construction. The intervals should be read alongside the arm-specific estimates and the study’s population and endpoint definitions, rather than as proof of equivalence or of a clinically important difference.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial’s original design calculations. For these binary outcome comparisons, the displayed figures are participants per arm. The registry record does not report the trial’s own original sample-size assumptions or justification.

The 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 to a stated fraction of the observed effect: 100%, 75%, or 50%. For time-to-event outcomes, the general convention would be total events, but these all-bleeding calculations are for participants per arm, not total events.

The 80% power column represents the planned number of participants per arm under the stated assumptions for a design with an 80% chance of detecting the chosen effect if that effect and the model assumptions hold. The 90% power column uses a higher target chance of detection, and therefore requires more participants per arm for a given effect assumption. These are design-planning interpretations, not guarantees about the result of a future study.

Read each comparison separately, because the observed contrasts differ and therefore yield different planning figures. Within a comparison, planning for 75% or 50% of the observed effect means planning for a smaller effect than the full observed contrast. Smaller effects are harder to detect and require more participants per arm under the same assumptions. The curve conveys the same general relationship between assumed effect size and planning requirement as the listed figures.

This is not observed power. It is a forward-looking illustration using the observed effect as an input; it does not measure the probability that the completed trial detected an effect that was truly present.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.203; treatment proportion p₁ = 0.237; average p̄ = 0.220.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5858 = 1.1482.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5853 = 0.4926.
4. n = (1.1482 + 0.4926)² / (0.0350)² = 2,201.9, rounded up to 2,202 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 <- 0.20253164556962                          # control proportion
p1 <- 0.2375                          # 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(806624)
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 = 2,202 (80% power), 2,948 (90% power)
 75% of observed effect: n per arm = 3,860 (80% power), 5,166 (90% power)
 50% of observed effect: n per arm = 8,556 (80% power), 11,454 (90% power)
power.prop.test: 2201.9 
Simulated power at n = 2,202 per arm: 0.794 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The sponsor-reported results are differences in percentages with 95% confidence intervals. The registry gives -3.5 percentage points for DU176b 30mg compared with DU-176b 60 mg, -9.1 for DU176b 30mg compared with Warfarin Potassium, and -5.6 for DU-176b 60 mg compared with Warfarin Potassium. Their respective intervals are -16.2 to 9.4, -22.4 to 4.5, and -19.3 to 8.2.

The registry record does not report a p-value or a named statistical method for these sponsor comparisons. The additional calculations are simple unadjusted re-calculations from posted summary statistics, with p-values of 0.595 and 0.191 for the comparisons against DU176b 30mg. These do not replace the sponsor’s reported results and may not use the same method. The record indicates no discrepancy between the sponsor analyses and the additional calculations; nevertheless, the sponsor-reported analyses remain the registry’s own reported comparisons. The re-calculations should be understood as supplementary, not as a basis for asserting a different sponsor result.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists three sponsor-reported pairwise comparisons among the three arms. When multiple comparisons are examined, the chance of obtaining at least one apparently unusual result can increase if each comparison is assessed separately. Statistical methods can address this issue through prespecified testing strategies or adjustments, but the registry record does not report whether multiplicity was considered or how it was handled. The sponsor comparisons have no posted p-values, so their inferential testing approach cannot be assessed from the reported results.

The registry also does not report whether the sponsor’s comparison estimates were adjusted for baseline characteristics or other covariates. The additional recalculations are explicitly unadjusted. A reader should therefore distinguish the group-level descriptive percentages, the sponsor-reported contrasts, and the supplemental unadjusted comparisons rather than treating them as interchangeable analyses.

The primary endpoint population is defined as subjects who received at least one dose and had at least one post-dose safety assessment, with the endpoint analyzed among those who proceeded to the treatment period. This is useful information, but the record does not give a detailed account of missing data, withdrawals, endpoint ascertainment, or the handling of subjects without a post-dose assessment. It does not report whether any imputation or sensitivity analysis was used.

The registry does not state that the primary analysis followed an intention-to-treat approach, and that approach should not be assumed. Nor does it report whether analysis populations differed for the secondary outcomes. The arm denominators posted for the primary outcome are 79.0, 80.0, and 75.0; the record does not provide a complete participant-flow explanation for those denominators relative to enrollment.

These gaps matter because missing outcomes, population definitions, and multiplicity decisions can affect how confidently a group comparison is interpreted. Their absence from the registry record does not establish that the procedures were not used; it means they are not reported in the registry record.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure (2.5%), cardiac failure congestive (1.3%), upper gastrointestinal haemorrhage (1.3%), hypertensive crisis (1.3%), colonic polyp (1.3%).

The serious adverse event figures report 3 affected subjects among 79 at risk in the DU176b 30mg group, 10 among 80 in the DU-176b 60 mg group, and 5 among 75 in the Warfarin Potassium group. These are counts of subjects with serious adverse events, not the primary all-bleeding percentages. The registry also reports other adverse events affecting 62 of 79, 65 of 80, and 59 of 75, respectively. The record does not report death counts.

The listed leading serious adverse event terms include Cardiac failure at 2.5%, cardiac failure congestive at 1.3%, Upper gastrointestinal haemorrhage at 1.3%, Hypertensive crisis at 1.3%, Colonic polyp at 1.3%, and Pneumonia at 1.3%. These terms and percentages are reported as listed; the registry does not explain whether related terms were grouped or how the percentages were calculated.

General interpretation: serious adverse event counts summarize events classified as serious, while the primary endpoint counts all bleeding categories. They are different safety summaries and should not be combined. The counts alone do not establish that an event was caused by a treatment, and the registry record does not provide enough detail to assess event timing, severity patterns, or attribution.

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

The posted results show all-bleeding percentages of 20.3% for DU176b 30mg, 23.8% for DU-176b 60 mg, and 29.3% for Warfarin Potassium. The arm confidence intervals are broad, and all three sponsor-reported comparison intervals include zero. The registry’s pairwise estimates therefore do not provide a precise separation among the groups on this endpoint.

That statistical description is narrower than a claim that the treatments are the same or different in a clinically meaningful way. A confidence interval that includes zero does not prove equivalence. Equivalence or non-inferiority would require an appropriate design, prespecified margin, and analysis information; such information is not reported in the registry record. Likewise, the observed percentages alone do not establish why the values differ.

The primary endpoint combines major, clinically relevant non-major, and minor bleeding. It does not tell the reader how the result divides among those categories. The outcome is reported for a Safety Analysis Set defined by treatment exposure and a post-dose safety assessment, and for subjects who proceeded to the treatment period. Generalization should take that population definition into account.

The record describes treatment administration for 12 weeks but gives a 6-month timeframe for the primary endpoint. It does not explain how those timing descriptions relate. Other important details—including the sponsor’s comparison method, missing-data handling, multiplicity approach, and analysis plan—are not reported in the registry record.

Overall, the registry offers group estimates and uncertainty intervals for an all-bleeding safety outcome in this Phase 2 study. Those results are descriptive and comparative evidence for the study population and endpoint as recorded. They should not be read as medical advice or as a definitive conclusion about treatment effects beyond the reported analyses.

17. Why This Trial Matters Statistically

This trial illustrates why a group percentage and a group comparison answer related but distinct questions. The arm percentages describe the observed incidence in each group, while a difference in percentages directly expresses the contrast between two groups. Both need uncertainty intervals to show how much precision the data support. Here, the sponsor-reported intervals include zero and span differences in either direction, so the point estimates alone are not enough to characterize the contrasts precisely.

The endpoint also demonstrates how the definition of an outcome shapes interpretation. “All bleeding” combines major, clinically relevant non-major, and minor events. That makes the result broader than a major-bleeding-only outcome, but it leaves the category-specific incidence unavailable in the posted primary results. Knowing the event definition and the analysis population is essential before interpreting the percentages.

Several design and reporting details are relevant statistically: random allocation, a parallel-group structure, an active warfarin control, and a defined Safety Analysis Set. At the same time, the registry does not report the comparison method, multiplicity handling, missing-data procedures, or the original sample-size rationale. These omissions show why a result should be read with both its estimates and its analysis documentation in view.

The sample-size illustrations further highlight the difference between planning and inference. They use fractions of the observed effect and stated assumptions to show how planning requirements change as the target effect changes. They are not observed power and do not change the uncertainty in the completed trial’s estimates.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the statistical method used for the sponsor’s pairwise comparisons, and it gives no p-values for those results. The methods used for confidence intervals are also not identified. This limits independent assessment of how the sponsor estimates were constructed. The supplementary calculations are unadjusted and should not be assumed to reproduce the sponsor’s method.

The handling of missing data, withdrawals, and absent safety assessments is not reported in the registry record. Although the Safety Analysis Set and the endpoint analysis population are defined, a detailed account of participant flow into those analyses is not provided. The record also does not report an intention-to-treat analysis or a sensitivity analysis for missing outcomes.

Multiplicity procedures are not reported despite the three pairwise sponsor comparisons. The trial’s original sample-size justification and design assumptions are also not reported, so the planning illustrations based on observed effects cannot be treated as the original rationale for enrollment.

The registry describes DU-176b treatment for 12 weeks and lists the primary endpoint timeframe as 6 months without clarifying how those periods relate. The primary all-bleeding result combines bleeding severity categories, and the posted primary results do not give category-specific estimates. The registry record does not report death counts in the adverse-event summary. These limitations constrain interpretation of timing, event composition, and the wider safety picture.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: DU-176b Phase 2 Dose Finding Study in Subjects With Non-valvular Atrial Fibrillation — NCT00806624.
• Registry record last updated 2019-02-26; status last verified 2015-01.
• Results first posted 2015-01-26.
• 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

NCT00806624 is a completed, randomized, parallel-group Phase 2 study of two fixed DU-176b doses and warfarin in subjects with non-valvular atrial fibrillation. The registry records enrollment of 234 and describes male and female subjects aged 18 to 80 years, inclusive, with a CHADS2 Score of at least 1.

The primary endpoint was incidence of all bleeding—major, clinically relevant non-major, and minor—reported as a percentage of subjects with bleeds. Arm estimates were 20.3% for DU176b 30mg, 23.8% for DU-176b 60 mg, and 29.3% for Warfarin Potassium. The sponsor-reported comparison intervals all include zero.

The endpoint analysis used the defined Safety Analysis Set among subjects who proceeded to the treatment period. The record describes 12 weeks of DU-176b administration and a 6-month primary endpoint timeframe. Details of the sponsor’s comparison method, missing-data handling, multiplicity procedures, and original sample-size justification are not reported in the registry record.