Lopinavir/r or Fosamprenavir/r Switch to Atazanavir/r or Darunavir/r: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lopinavir/r or Fosamprenavir/r Switch to Atazanavir/r or Darunavir/r (NCT00756730), a randomized phase 4 study. The primary outcome is Percentage of Patients That Experience 10% Decline in Triglycerides From Baseline to Week 24..

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group phase 4 trial of switching protease inhibitor regimens. Participants taking lopinavir/ritonavir or fosamprenavir/ritonavir were assigned to switch to either darunavir/ritonavir or atazanavir/ritonavir, with background nucleoside reverse transcriptase inhibitors. The registry lists enrollment as 49 and the trial status as completed. The listed start and primary completion dates are 2008-09 and 2011-06.

The two arms used once-daily regimens: darunavir/ritonavir at 800mg/100mg and atazanavir/ritonavir at 300mg/100mg. The primary endpoint was assessed from baseline to week 24 and expressed as the percentage of participants with at least a 10% triglyceride decline. The arm descriptions say the switch was intended to improve triglycerides while maintaining virological suppression. Secondary outcomes included HIV viral load below 200 copies/mL at week 4, 12 and 24; CD4 change from baseline to week 24; and total, LDL and HDL cholesterol measures.

Open-label means treatment assignment was not masked. That matters when interpreting outcomes that may depend on assessment or behavior, although triglyceride concentration is a laboratory measure. Random allocation can reduce systematic differences between arms at assignment, but it cannot guarantee balanced groups in a small trial or remove uncertainty from the observed estimates. The record does not report the randomization procedure, allocation concealment, the detailed analysis population, or a protocol-defined statistical analysis plan. The original sample-size assumptions and any planned interim analyses 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: Two patients in the ATV/r arm discontinued prior to week 24: 1 due to a grade 2 rash, and one due to low level viremia. Neither subject met criteria for virologic failure.

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 Percentage of Patients That Experience 10% Decline in Triglycerides From Baseline to Week 24., measured over baseline, 24 weeks.

The primary endpoint counted the percentage of participants who experienced a triglyceride decline of at least 10% between baseline and week 24. The registry description says this threshold was considered clinically significant. A binary endpoint reduces each participant’s triglyceride change to whether the threshold was reached, making the arm comparison a comparison of proportions rather than of average triglyceride changes.

This kind of endpoint can make a clinically chosen threshold easy to interpret: it asks how often participants crossed that threshold, rather than how large the average change was. It also discards information about the amount of change within each category. A participant just below the threshold and one with no decline are both counted as not meeting the endpoint; a participant just above it and one with a much larger decline are both counted as meeting it. The registry record does not report the continuous triglyceride summaries that would show the distribution or average change in each arm.

The record reports 80.0% reaching the endpoint in the darunavir/ritonavir arm and 73.0% in the atazanavir/ritonavir arm. The endpoint is about triglyceride change at week 24. It does not, on its own, establish the effect on viral suppression, other lipid measures, adverse events, or outcomes beyond the stated assessment period.

7. Results Posted in the Registry

• Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD: 72.7% (16/22) versus 80.0% (20/25) on control; risk difference -7.3 percentage points (95% CI -31.6 to 17.1), risk ratio 0.91 (0.66–1.25); unadjusted two-proportion z-test p = 0.557.

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.

Difference in CD4 From Baseline to Week 24

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD: mean 14.28 versus 10.75 on control; difference 3.53 (95% CI -48.44 to 55.50), standardized effect d = 0.04; z-test p = 0.894.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Switch to Atazanavir/Ritonavir (ATV/r), 300mg/100mg QD and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the questions beyond triglyceride response. They cover viral-load status at stated follow-up times, CD4 change, and cholesterol measures. These outcomes relate to the primary question because the trial description frames a switch as a way to improve triglycerides while maintaining virological suppression. They address different aspects of the treatment comparison, however, and cannot be collapsed into a single conclusion about the primary endpoint.

The posted CD4 comparison has a mean difference of 3.53 cells/mm^3, with a confidence interval from -48.44 to 55.5 and an unadjusted p-value of 0.894. That interval crosses zero and includes a broad range of possible differences. The registry lists additional secondary outcomes, but does not provide secondary comparison estimates for viral-load status or the cholesterol outcomes in the record summarized by these results. Their results are therefore not reported in the registry record.

Secondary outcomes are often numerous and may be assessed at multiple time points. When many comparisons are made, the chance of finding at least one apparently notable result by chance can rise unless multiplicity is addressed. The registry record does not report a multiplicity adjustment or a hierarchy of confirmatory and exploratory outcomes. Unadjusted secondary results should consequently carry less weight than a prespecified primary analysis, especially when estimates are imprecise or results are not fully reported.

The secondary endpoints can help characterize the range of outcomes measured, but they do not repair uncertainty in the primary comparison. Nor does a lack of posted results for some outcomes establish that those outcomes were unchanged. Their absence from the registry results should be distinguished from a reported null finding.

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

• Percent of Patients With HIV VL <200 Copies/mL at Week 4, 12 & 24
• Difference in CD4 From Baseline to Week 24
• Total Cholesterol in the Two Study Groups at 24 Weeks
• LDL Cholesterol at Week 24
• HDL Cholesterol at Week 24

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant either reached the 10% triglyceride decline threshold by week 24 or did not. For a binary outcome, the arm-level percentage is the proportion of participants who had the event. The comparison reported for the primary endpoint is a risk difference, which expresses the difference between the two event proportions. A value of zero represents equal proportions. A negative value in this comparison means the observed proportion in the atazanavir/ritonavir arm was lower than the observed proportion in the darunavir/ritonavir arm.

What does the confidence interval express?

A confidence interval describes uncertainty around an estimated effect under the statistical method used. It is not a range that guarantees the true effect lies within it, nor is it a probability statement about the treatment effect. For a risk difference, an interval that includes zero leaves no-difference values compatible with the data at the interval’s stated confidence level. Here, the posted interval for the primary comparison extends across zero. Its width also shows that the data are compatible with a substantial range of possible differences. The registry record does not specify the confidence level or the exact interval method in its narrative, so those details should not be inferred from the interval alone.

How should the p-value be read?

The posted unadjusted p-value is 0.557. In general, a p-value measures how well the observed data accord with a specified null model, assuming the model and test conditions are appropriate. It is not the probability that the null hypothesis is true, and it is not a measure of clinical importance. A relatively large p-value does not demonstrate equivalence or prove the absence of a difference. Equivalence or non-inferiority requires a prespecified margin and an analysis designed for that question; such a margin and analysis are not reported in the registry record.

Why does an unadjusted comparison matter?

An unadjusted comparison uses the posted group summaries without controlling for other variables. It can be a transparent way to describe the observed contrast, but it cannot show whether adjustment for baseline characteristics would change the estimate. No adjusted primary analysis is listed in the registry record. The reported comparison is therefore best understood as a simple summary-based comparison, not as evidence that all possible covariate or missing-data concerns have been addressed. The record does not report the prespecified analysis plan or the method used for any investigator analysis.

What does over-dispersion mean for counts?

Over-dispersion is a general issue in count outcomes: it occurs when observed variability exceeds what a simple model assumes. It can make standard errors too small if the model does not allow for that extra variability. The primary endpoint is a binary proportion, not a count rate, and the registry does not report an over-dispersion model for it. This concept is therefore not a special feature of the posted primary analysis. More generally, statistical methods should match the outcome’s scale and variability rather than be chosen by default.

How should the secondary continuous comparison be read?

The posted CD4 outcome is a mean change from baseline to week 24, with standard error reported for each arm. A mean summarizes the average observed change; a standard error describes uncertainty in that estimated mean, rather than the spread of individual participant values. The registry reports a mean difference of 3.53 cells/mm^3 for atazanavir/ritonavir relative to darunavir/ritonavir, with a confidence interval from -48.44 to 55.5 and an unadjusted p-value of 0.894. The interval crosses zero and is wide, so it does not identify a precise between-arm difference.

The registry also gives a standardized effect size for the CD4 comparison. In general, standardization expresses a mean difference relative to a measure of variability, which can help compare scales but does not replace the original-unit estimate. The posted standardized value is 0.039. It should not be mistaken for a direct clinical interpretation of CD4 change, and the record does not report an adjusted analysis for this endpoint.

What can planning calculations tell us?

Planning illustrations use an assumed effect and statistical assumptions to estimate how many participants per arm would be needed for a target power. They are not observed trial outcomes, and they do not explain how the original investigators designed this trial. The registry gives assumptions for the posted illustrations: a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect set to a stated fraction of the observed effect. General statistical power is the probability of detecting a specified effect if that effect is present and the analysis assumptions hold. The original trial’s design assumptions, including any planned effect size, are not reported in the registry record.

11. Confidence Intervals and Precision

The primary arm estimates are 80.0% in the darunavir/ritonavir group and 73.0% in the atazanavir/ritonavir group. The estimated risk difference for atazanavir/ritonavir relative to darunavir/ritonavir is -0.073. Its confidence interval ranges from -0.316 to 0.171. Because the interval crosses zero, it includes no difference, while also allowing for effects in either direction. Its breadth indicates that the posted data do not pin down the size or direction of the population difference with precision.

The interval should be considered alongside the modest group sizes and the missing-outcome information. The endpoint summaries list 25 participants in the darunavir/ritonavir arm and 22 in the atazanavir/ritonavir arm. The registry notes two discontinuations before week 24 in the latter arm, but does not state how endpoint data for those participants were handled. The record does not report a missing-data sensitivity analysis or an imputation method. These gaps limit how fully the interval can be evaluated.

The CD4 mean-difference interval is also broad, extending from -48.44 to 55.5 cells/mm^3 around a reported mean difference of 3.53 cells/mm^3. It includes zero and values on either side. This conveys uncertainty rather than evidence that the groups are identical. Confidence intervals are not substitutes for judging endpoint relevance or study limitations, but they make clear that the posted estimates are not highly precise.

The confidence intervals reflect the posted summary comparisons and their statistical assumptions. The registry record does not report adjusted estimates or additional analyses that could clarify robustness. Thus, the intervals describe uncertainty in the reported comparisons, not every source of uncertainty in study conduct, measurement, or generalizability.

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 expressed as participants per arm, not as total events. They are illustrations based on the observed effect and specified assumptions, not a report of the trial’s original design calculation. The assumptions listed for these calculations are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original design assumptions are not reported in the registry record.

For the primary binary outcome, the planning illustration for 100% of the observed effect gives 535 participants per arm for 80% power and 716 participants per arm for 90% power. For planning for 75% of the observed effect, the corresponding figures are 926 and 1,239 participants per arm. For planning for 50% of the observed effect, they are 2,024 and 2,709 participants per arm.

In plain terms, 80% power means that, if the effect used in the calculation were the true effect and the assumptions held, repeated studies of the planned size would detect that effect at the stated significance level about 80% of the time. The 90% power column uses a higher chance of detecting that specified effect, and therefore calls for a larger planned sample. Smaller effects need more participants to distinguish them from random variation with the same target power.

These values are not observed power. They are planning illustrations based on an effect estimated from this trial, and that observed estimate is itself uncertain. They should not be read as the number of participants the investigators intended to enroll or as proof that the trial was adequately or inadequately designed.

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 = 0.800; treatment proportion p₁ = 0.727; average p̄ = 0.764.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6008 = 1.1776.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5986 = 0.5038.
4. n = (1.1776 + 0.5038)² / (-0.0727)² = 534.5, rounded up to 535 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 <- 0.8                          # control proportion
p1 <- 0.727272727272727                          # 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(756730)
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 = 535 (80% power), 716 (90% power)
 75% of observed effect: n per arm = 926 (80% power), 1,239 (90% power)
 50% of observed effect: n per arm = 2,024 (80% power), 2,709 (90% power)
power.prop.test: 534.5 
Simulated power at n = 535 per arm: 0.801 (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 lists several secondary outcomes, including viral-load status at week 4, 12 and 24, CD4 change, and total, LDL and HDL cholesterol outcomes. It reports eight outcome measures and no reported analyses. The multiplicity plan—whether outcomes were prioritized, adjusted, or treated as exploratory—is not reported in the registry record. This matters because examining multiple outcomes can increase the chance that at least one result appears unusual by chance. Unadjusted p-values should be interpreted with that context in mind.

The record does not report the original statistical analysis plan, a prespecified hierarchy of endpoints, or an adjustment for multiple comparisons. It also does not report whether interim analyses were planned or conducted. No assumptions about those procedures can be made from the posted results alone. The absence of a reported adjustment does not prove that none was performed outside the registry; it means the registry record does not document one.

Missing outcome handling is another important uncertainty. The record says two participants in the atazanavir/ritonavir arm discontinued before week 24, one because of a grade 2 rash and one because of low-level viremia, and states that neither met criteria for virologic failure. It does not describe whether their week-24 triglyceride outcomes were observed, excluded, imputed, or handled by another method. It also does not report a primary-outcome sensitivity analysis that would show how alternative assumptions about missing values affect the comparison.

The primary endpoint summaries use 25 participants in the darunavir/ritonavir arm and 22 in the atazanavir/ritonavir arm, while the adverse-event summaries list 25 and 24 at risk, respectively. These are endpoint-specific reported figures; the record does not explain the analysis-population definitions behind the difference. It does not specify whether the primary analysis was intention-to-treat, per-protocol, or another population. The registry record also does not report detailed exclusion criteria or a participant flow account. Those omissions limit assessment of how closely the comparison preserves the randomized assignment.

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: possible bowel obstruction (4.2%), alcohol withdrawal/suicidal ideation (4.2%), urosepsis (4.0%).

The adverse-event summaries list one serious event in each arm among those reported at risk: 1 of 25 in the darunavir/ritonavir arm and 1 of 24 in the atazanavir/ritonavir arm. The summaries also list other adverse events affecting 7 of 25 and 8 of 24, respectively. These are event counts and denominators as recorded; they do not establish that events were caused by the assigned regimen. The registry record does not report deaths.

The serious-event terms listed include possible bowel obstruction at 4.2%, alcohol withdrawal/suicidal Ideation at 4.2%, and urosepsis at 4.0%. The record does not provide enough detail to infer timing, relatedness, recurrence, or differences in risk between arms from these terms alone. The event summaries should be read as descriptive safety reporting, not as a comparative safety test. The adverse-event denominators also differ from the primary endpoint arm sizes, and the registry does not explain the analysis populations behind that difference.

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

The posted primary results show that 80.0% of the darunavir/ritonavir arm and 73.0% of the atazanavir/ritonavir arm experienced the defined 10% triglyceride decline by week 24. The unadjusted risk-difference comparison has a confidence interval that crosses zero and a p-value of 0.557. These findings do not establish a statistically clear difference between the arms, but neither do they establish equivalence. The interval remains compatible with differences in either direction, and the estimate is imprecise.

The result answers a narrow question: how often participants in these two randomized switch groups reached a specified triglyceride threshold by the stated follow-up. It does not compare either switch with continuation of lopinavir/ritonavir or fosamprenavir/ritonavir. It also does not settle whether viral suppression was maintained, since the primary endpoint is not a virological endpoint. Although viral-load status was listed as a secondary outcome, the corresponding outcome results are not reported in the registry record.

The findings should not be extended automatically to people outside the described study population or to other treatment regimens and follow-up periods. The trial was open-label, had limited enrollment, and has incomplete reporting about missing primary endpoint values and the analysis population. The registry does not report the protocol’s original sample-size assumptions or a detailed statistical analysis plan. These limitations affect how confidently the posted estimates can be interpreted.

In statistical terms, a non-significant comparison is not proof that the two options produce identical outcomes. Equivalence requires a prespecified margin and a design and analysis suited to demonstrating that differences are sufficiently small; those elements are not reported. Likewise, the observed arm percentages are not a guarantee of what would happen in another study. They are estimates from this trial, with considerable uncertainty around their comparative interpretation.

17. Why This Trial Matters Statistically

This trial illustrates why an observed difference in arm percentages should not be interpreted without its uncertainty. The reported primary proportions differ, but the risk-difference interval includes zero and spans effects in either direction. The unadjusted p-value does not provide strong evidence against a no-difference model, while the interval makes clear that the estimate remains imprecise. Reading the point estimate, interval, and analysis context together is more informative than treating any single statistic as decisive.

The endpoint also illustrates a trade-off in statistical design. A threshold such as a 10% triglyceride decline gives a readily interpretable binary outcome, but it discards how far each participant’s triglyceride level changed. That loss of detail can obscure variation within the groups and makes the result depend on the chosen threshold. The registry description states why this threshold was selected, but does not report continuous triglyceride summaries alongside the primary endpoint.

The trial’s small enrollment relative to the planning illustrations emphasizes the distinction between an observed result and the information needed to estimate an effect precisely. The planning calculations are not the trial’s original design justification, and they cannot establish what the investigators intended. Their value is to show how sample-size requirements change when the target effect is smaller or the desired power is higher.

Finally, registry completeness is part of statistical interpretation. Missing-data handling, analysis populations, multiplicity procedures, and original design assumptions can all affect how results should be evaluated. When these details are not reported, conclusions should remain tied to the posted summaries and their stated limitations.

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.

Several limitations are specific to the available record. The primary endpoint is a binary threshold outcome, and continuous triglyceride changes by arm are not reported. This prevents assessment of the magnitude and variability of triglyceride changes beyond whether participants crossed the 10% threshold.

The registry notes two discontinuations before week 24 in the atazanavir/ritonavir arm, with reasons given, but does not state how these participants’ primary endpoint outcomes were handled. The primary summaries list 22 participants for that arm, whereas the adverse-event summary lists 24 at risk. The record does not explain the difference in denominators or define the analysis populations. No missing-data sensitivity analysis is reported.

The posted primary comparison is an unadjusted recalculation from summary statistics, and the registry lists no reported analyses. No adjusted primary result is available in the record. The trial’s original sample-size assumptions, detailed analysis plan, randomization procedure, and allocation-concealment process are not reported in the registry record. The record also does not report whether interim analyses were planned or whether multiplicity was addressed.

Secondary outcome reporting is incomplete in the available results: viral-load and cholesterol outcomes are listed, but their comparative findings are not reported in the registry record. The safety summaries provide counts and several serious-event terms but do not establish causality or supply detailed comparative analyses. These reporting limitations mean that the posted primary result cannot stand in for a complete assessment of virological, lipid, or safety outcomes.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Lopinavir/r or Fosamprenavir/r Switch to Atazanavir/r or Darunavir/r — NCT00756730.
• Registry record last updated 2017-08-21; status last verified 2017-07.
• Results first posted 2012-07-13.
• 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

The registry describes a completed, randomized, open-label, parallel-group phase 4 trial in people with HIV and elevated triglycerides while receiving lopinavir/ritonavir or fosamprenavir/ritonavir. Participants switched to once-daily darunavir/ritonavir or atazanavir/ritonavir, with background nucleoside reverse transcriptase inhibitors. Enrollment was 49.

The primary endpoint was the percentage experiencing a 10% triglyceride decline from baseline to week 24. The posted proportions were 80.0% for darunavir/ritonavir and 73.0% for atazanavir/ritonavir. The unadjusted comparison was imprecise and did not establish a clear difference. Missing-data handling, original design assumptions, and a detailed analysis plan are not reported in the registry record.