This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the registry-reported CELESTIAL registry data.
1. Trial at a Glance
CELESTIAL was a randomized, parallel, quadruple-masked phase 3 trial evaluating cabozantinib tablets versus placebo in subjects with hepatocellular carcinoma who had received prior sorafenib. The trial enrolled 707 randomized subjects and posted statistical analyses for overall survival, progression-free survival, and objective response rate.
| Feature | CELESTIAL |
|---|---|
| Phase | Phase 3 |
| Condition | Hepatocellular carcinoma |
| Brief title | Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib |
| Design | Randomized, parallel, quadruple-masked |
| Allocation | Randomized |
| Primary purpose | Treatment |
| Enrollment | 707 |
| Primary endpoint | Overall Survival (OS) |
| Primary endpoint type | Time-to-event |
| Hypothesis type | Superiority |
| Trial status | Completed |
| Lead sponsor | Exelixis |
| Sponsor type | Industry |
| ClinicalTrials.gov | NCT01908426 |
2. Clinical Question
The central statistical question was whether randomized treatment with cabozantinib tablets differed from placebo with respect to the primary time-to-event endpoint, overall survival, in subjects with hepatocellular carcinoma who had received prior sorafenib.
Population
Subjects with hepatocellular carcinoma who had received prior sorafenib.
Intervention
Cabozantinib tablets (XL184).
Comparator
Placebo tablets.
Primary question
Does cabozantinib produce a different overall-survival experience from placebo under the prespecified superiority analysis?
This framing is important because the primary endpoint is a time-to-event outcome rather than a simple binary outcome. The analysis therefore uses methods that account for both the timing of deaths and right-censoring rather than reducing every patient to a single yes/no response indicator.
3. Trial Design
Cabozantinib
- Cabozantinib tablets (XL184)
- Randomized treatment arm
Placebo
- Placebo tablets
- Randomized comparator arm
The statistical analysis population for the second interim OS analysis was explicitly the intention-to-treat population, consisting of all 707 randomized subjects: 470 assigned to cabozantinib and 237 assigned to placebo.
4. Trial Timeline
Trial start
The registry lists 26 September 2013 as the study start date.
OS interim-analysis data cutoff
The primary OS analysis was based on a second planned interim analysis with a data cutoff of 01 June 2017.
Primary completion
The registry lists 16 October 2017 as the primary completion date.
5. Endpoints
| Endpoint | Registry time frame | Type | Analysis method |
|---|---|---|---|
| Overall Survival (OS) | Up to 45 months | Time-to-event | Stratified log-rank test; hazard ratio |
| Progression-Free Survival (PFS) | Up to 45 months | Time-to-event | Stratified log-rank test; hazard ratio |
| Objective Response Rate (ORR) | ORR is measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation of study treatment (up to 45 months) | Binary | Cochran-Mantel-Haenszel test |
Overall Survival
The primary analysis of OS is defined as the time from randomization to death from any cause. The analysis was based on a second planned interim analysis prespecified to be performed at approximately the 75% information fraction, at approximately 466 deaths. The data cutoff date for this event-driven analysis in the ITT population was 01 June 2017.
Progression-Free Survival
PFS was a secondary endpoint with a registry time frame of up to 45 months. The prespecified primary analysis of PFS was based on the first 707 randomized subjects: 470 cabozantinib and 237 placebo.
Objective Response Rate
ORR was measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation. The analysis was performed in the ITT population, with response determined by Investigator per RECIST 1.1.
6. Statistical Methodology
Intention-to-treat analysis
The ITT population included all 707 randomized subjects for the second interim OS analysis. This approach preserves the treatment comparison created by randomization: subjects remain associated with the group to which they were randomized rather than being reassigned according to subsequent treatment exposure or outcome.
For this trial, the ITT principle is especially important because the OS comparison concerns the effect of the randomized treatment strategy. An ITT estimate therefore answers a different question from an analysis restricted to patients who remained on treatment.
Stratified log-rank testing
The OS log-rank test was stratified by etiology of disease, geographic region, presence of extrahepatic spread of disease and/or macrovascular invasion. The PFS log-rank test used the same stated stratification factors.
The log-rank test compares the observed pattern of events between treatment groups across follow-up. Stratification allows the comparison to account for prespecified factors rather than treating all randomized subjects as if they came from a single homogeneous stratum.
Hazard ratio
The reported effect measure for OS and PFS was the hazard ratio. A hazard ratio below 1 indicates a lower estimated instantaneous event rate in the cabozantinib group relative to placebo under the fitted time-to-event comparison.
The hazard ratio is a relative time-to-event measure. It is not itself a probability, an absolute risk difference, or a statement that every individual subject experiences the same proportional change in risk.
Cochran-Mantel-Haenszel analysis
ORR was analyzed with a Cochran-Mantel-Haenszel test in the ITT population. This is a categorical-data method that can evaluate treatment-group differences while accounting for stratification when the analysis is specified in that form.
Superiority testing
The trial's stated hypothesis type was superiority. The inferential objective was therefore to determine whether the randomized treatment groups differed, rather than to demonstrate that cabozantinib was sufficiently close to placebo within a prespecified non-inferiority margin.
7. Primary Result: Overall Survival
The primary endpoint analysis compared overall survival between cabozantinib and placebo in the ITT population. The analysis used the stratified log-rank test and reported a hazard ratio with a two-sided 95% confidence interval.
Hazard ratio for overall survival
95% CI: 0.63–0.92 · P = 0.0049
Superiority analysis; ITT population; second planned interim analysis.
| Primary endpoint | Cabozantinib | Placebo | Effect estimate | P-value |
|---|---|---|---|---|
| Overall Survival (OS) | 470 randomized | 237 randomized | HR 0.76 95% CI 0.63–0.92 |
0.0049 |
An OS hazard ratio of 0.76 means that, under the time-to-event model used for this analysis, the estimated instantaneous hazard of death in the cabozantinib group was 76% of that in the placebo group. Expressed as a simple relative-hazard interpretation, this corresponds to an estimated 24% lower hazard of death.
The HR does not mean that 24% of patients were saved, that each individual patient's risk fell by exactly 24%, or that the absolute probability of death was reduced by 24 percentage points. A hazard ratio is a relative measure of event rates over time.
The two-sided 95% confidence interval of 0.63–0.92 describes the statistical uncertainty around the estimated HR under the analysis framework. Because the entire interval is below 1, the reported interval is consistent with a lower estimated hazard in the cabozantinib group relative to placebo.
The P-value of 0.0049 addresses the strength of evidence against the specified null hypothesis under the statistical testing framework. It does not measure the size of the treatment effect, the probability that the treatment works, or the clinical importance of the observed HR.
The result also comes from a planned interim analysis, not simply an unplanned look at accumulating data. The registry states that this was the second planned interim analysis at approximately the 75% information fraction and approximately 466 deaths. That design context matters when interpreting the inferential result.
8. Secondary Result: Progression-Free Survival
PFS was analyzed in the prespecified primary analysis based on the first 707 randomized subjects, with 470 assigned to cabozantinib and 237 to placebo. The registry reports a stratified log-rank analysis and a hazard ratio as the effect measure.
Hazard ratio for progression-free survival
95% CI: 0.36–0.52 · P < 0.0001
Superiority analysis; stratified log-rank test.
| Secondary endpoint | Cabozantinib | Placebo | Effect estimate | P-value |
|---|---|---|---|---|
| Progression-Free Survival (PFS) | 470 randomized | 237 randomized | HR 0.44 95% CI 0.36–0.52 |
< 0.0001 |
A PFS hazard ratio of 0.44 means that the estimated instantaneous hazard of the PFS event in the cabozantinib group was 44% of the corresponding hazard in the placebo group. In relative terms, this is an estimated 56% lower hazard of the PFS event.
This does not mean that 56% of patients avoided progression or death. PFS is a time-to-event endpoint, and the HR summarizes a relative comparison of event hazards rather than an absolute event probability.
The two-sided 95% CI of 0.36–0.52 gives the uncertainty interval for the estimated HR. The interval is relatively far below 1, indicating that the reported estimate is not close to the null value within this confidence interval.
The reported P-value of < 0.0001 indicates strong statistical evidence against the null hypothesis under the specified analysis. It should not be interpreted as a measure of how large the PFS effect is; the HR and its confidence interval provide the effect-size information.
As with OS, interpretation of the HR assumes that a single hazard ratio provides an appropriate summary of the treatment comparison over follow-up. The ClinicalTrials.gov record does not provide enough information to evaluate the proportional-hazards assumption directly.
9. Secondary Result: Objective Response Rate
ORR was measured by radiologic assessment every 8 weeks after randomization until disease progression or discontinuation. The analysis was performed in the ITT population, with response determined by Investigator per RECIST 1.1.
Cochran-Mantel-Haenszel test
Cabozantinib vs placebo; ITT population; superiority analysis.
| Secondary endpoint | Analysis population | Method | P-value |
|---|---|---|---|
| Objective Response Rate (ORR) | ITT: 470 cabozantinib, 237 placebo | Cochran-Mantel-Haenszel test | 0.0086 |
The reported P-value of 0.0086 is the formal comparison reported for ORR. It indicates evidence of a difference between the randomized treatment groups under the specified Cochran-Mantel-Haenszel analysis.
The ClinicalTrials.gov record does not provide the numerical response rate in each arm or a confidence interval for the response-rate difference. Therefore, this page does not infer or reconstruct those quantities.
This distinction is important statistically: a P-value can establish evidence against a null hypothesis without telling the reader the magnitude of the absolute difference. When an effect estimate and confidence interval are available, they provide additional information about the size and precision of the observed difference.
10. Serious Adverse Events
The ClinicalTrials.gov record reports serious adverse events by randomized arm as affected subjects over subjects at risk.
| Safety measure | Cabozantinib | Placebo |
|---|---|---|
| Serious adverse events | 232 / 467 | 87 / 237 |
The denominators in this safety measure are not identical to the randomized totals used in the ITT efficacy analysis. The reported serious-adverse-event figures therefore should be presented exactly as affected over at risk rather than silently treating 467 and 237 as the randomized sample sizes for every analysis.
11. Stratification and Why It Matters
The CELESTIAL OS and PFS analyses were stratified by three sets of factors: etiology of disease, geographic region, and presence of extrahepatic spread of disease and/or macrovascular invasion.
| Stratification factor | Role in reported analysis |
|---|---|
| Etiology of disease | Used to stratify the OS and PFS log-rank analyses. |
| Geographic region | Used to stratify the OS and PFS log-rank analyses. |
| Extrahepatic spread and/or macrovascular invasion | Used to stratify the OS and PFS log-rank analyses. |
Stratification does not mean that the treatment effect is estimated separately and independently within every subgroup. Instead, the analysis accounts for the prespecified strata when constructing the overall comparison.
This is especially useful in randomized trials when important prognostic characteristics may influence event timing. A stratified analysis can make the treatment comparison more closely aligned with the design used to randomize subjects.
12. Interim Analysis and Information Fraction
The primary OS analysis was based on a second planned interim analysis prespecified to occur at approximately the 75% information fraction, corresponding to approximately 466 deaths. The data cutoff was 01 June 2017.
Why use an interim analysis?
An event-driven trial can evaluate accumulating information before the final number of events has occurred. The interim analysis becomes part of the prespecified statistical design rather than an ad hoc examination of the data.
Why information fraction matters
For a time-to-event trial, statistical information is closely related to the number of observed events. The stated 75% information fraction therefore describes how much of the planned event information had accumulated at the interim analysis.
The registry data identify this as a planned interim analysis but do not provide a separate alpha-spending function or interim efficacy boundary in the ClinicalTrials.gov recordset. Accordingly, this page does not attribute a particular alpha-spending procedure or boundary to CELESTIAL.
13. Statistical Methods Explained
Why was a log-rank test used for OS and PFS?
OS and PFS are time-to-event endpoints. Subjects can experience events at different times, and some subjects may be censored before an event occurs. The log-rank test compares the treatment groups across the follow-up period while accounting for the timing of observed events. CELESTIAL used a stratified version based on the prespecified stratification factors.
What does an OS hazard ratio of 0.76 mean?
An HR of 0.76 means that the estimated instantaneous hazard of death in the cabozantinib group was 76% of that in the placebo group under the fitted time-to-event comparison. A useful relative interpretation is an estimated 24% lower hazard. It is not a 24-percentage-point reduction in mortality and does not imply the same effect for every patient.
Why is the confidence interval important?
The 95% CI of 0.63–0.92 places the estimated OS hazard ratio in the context of statistical uncertainty. The point estimate is 0.76, but the interval communicates that the data do not identify that value with infinite precision. It also shows that the entire reported interval lies below 1.
Why doesn't the P-value measure effect size?
The OS P-value of 0.0049 measures the evidence against the relevant null hypothesis under the statistical testing framework. It is not a scale for clinical magnitude. Two studies can have the same P-value with different effect sizes, and a very small P-value can occur with a modest effect when the information is sufficiently large.
Why was stratification used?
The log-rank analyses were stratified by disease etiology, geographic region, and the presence of extrahepatic spread and/or macrovascular invasion. Stratification incorporates these prespecified factors into the time-to-event comparison rather than ignoring the structure established in the trial design.
Why does the analysis population matter?
The OS and ORR analyses explicitly used the ITT population, while the serious-adverse-event ClinicalTrials.gov record use an affected/at-risk denominator of 467 for cabozantinib and 237 for placebo. A statistical estimate cannot be interpreted correctly without knowing which subjects were eligible for that particular analysis.
What is different about the ORR analysis?
ORR is a binary endpoint rather than a time-to-event endpoint. The registry reports a Cochran-Mantel-Haenszel analysis and a P-value of 0.0086. That is a different statistical framework from the stratified log-rank method used for OS and PFS because the underlying outcome structure is different.
14. Confidence Intervals and Effect Size
The CELESTIAL results illustrate why a complete statistical interpretation should present an effect estimate, its confidence interval, and the P-value together.
| Endpoint | Effect | 95% CI | P-value | What it communicates |
|---|---|---|---|---|
| Overall Survival | HR 0.76 | 0.63–0.92 | 0.0049 | Relative time-to-event effect, statistical uncertainty, and evidence against the null. |
| Progression-Free Survival | HR 0.44 | 0.36–0.52 | < 0.0001 | Relative time-to-event effect, statistical uncertainty, and evidence against the null. |
| Objective Response Rate | Not reported in the ClinicalTrials.gov record | Not reported in the ClinicalTrials.gov record | 0.0086 | Evidence of a treatment-group difference under the reported categorical analysis. |
For a hazard-ratio result, first identify the direction of the effect, then examine the magnitude of the HR, then examine the confidence interval, and finally interpret the P-value in the context of the prespecified design. This sequence prevents the P-value from becoming the only statistic considered.
15. Time-to-Event Endpoints and Censoring
OS and PFS are fundamentally different from fixed-time binary outcomes because each subject contributes information over time. A subject who has not experienced the event by the end of observed follow-up can still contribute information before censoring.
The survival function represents the probability that the event time T exceeds a given time t. Time-to-event methods use the observed event and censoring information rather than reducing the follow-up history to a single binary indicator.
For OS in CELESTIAL, the registry explicitly defines the event time as the time from randomization to death from any cause. This definition makes the randomized assignment and the time origin unambiguous for the primary analysis.
The ClinicalTrials.gov record does not provide individual censoring times or the underlying event-time dataset. Consequently, this page does not attempt to reconstruct Kaplan-Meier curves, median survival times, numbers at risk, or other quantities that require information beyond the reported summary statistics.
16. Primary Analysis Population
| Endpoint | Analysis population | Sample sizes |
|---|---|---|
| Overall Survival | ITT population; second interim analysis | 707 randomized: 470 cabozantinib, 237 placebo |
| Progression-Free Survival | First 707 randomized subjects | 470 cabozantinib, 237 placebo |
| Objective Response Rate | ITT population; all randomized subjects | 470 cabozantinib, 237 placebo |
The consistency of the randomized sample sizes across the reported efficacy analyses is useful because it makes clear that the principal efficacy results were not generated from a selectively treated subset. At the same time, the safety denominator for serious adverse events differs for cabozantinib, so efficacy and safety populations should not be conflated.
17. What the Hazard Ratios Do — and Do Not — Mean
The OS HR of 0.76 corresponds to an estimated 24% lower instantaneous hazard of death for cabozantinib relative to placebo under the reported model. It does not mean that 24% of subjects avoided death, that survival probability increased by 24 percentage points, or that the treatment effect was identical at every point in follow-up.
The PFS HR of 0.44 corresponds to an estimated 56% lower instantaneous hazard of the PFS event. It does not mean that 56% of subjects were free of progression or death, because a hazard ratio is not an absolute event-free proportion.
The OS confidence interval of 0.63–0.92 and the PFS confidence interval of 0.36–0.52 describe uncertainty around their respective HR estimates. They do not describe the range of treatment effects experienced by individual patients.
A complete interpretation therefore uses the hazard ratio as one component of the evidence. The endpoint definition, analysis population, stratification, interim-analysis context, confidence interval, and P-value all contribute to understanding what the reported estimate actually establishes.
18. Multiplicity and Multiple Endpoints
The ClinicalTrials.gov record identifies one primary endpoint, overall survival, and report progression-free survival and objective response rate as secondary analyses. The OS analysis also came from a planned second interim analysis.
| Endpoint | Role | Statistical method | Reported effect / result |
|---|---|---|---|
| Overall Survival | Primary | Stratified log-rank test | HR 0.76; 95% CI 0.63–0.92; P = 0.0049 |
| Progression-Free Survival | Secondary | Stratified log-rank test | HR 0.44; 95% CI 0.36–0.52; P < 0.0001 |
| Objective Response Rate | Secondary | Cochran-Mantel-Haenszel test | P = 0.0086 |
The ClinicalTrials.gov record does not provide the complete multiplicity-adjustment procedure or an alpha-allocation scheme for the three posted analyses. Therefore, the reported P-values should be interpreted as the values attached to their respective registry analyses rather than reverse-engineering an unreported familywise-error procedure.
19. Missing Data and Analysis Assumptions
The ClinicalTrials.gov record identifies the ITT analysis populations and the statistical methods, but they do not provide a missing-data or imputation specification for the reported efficacy analyses.
For time-to-event endpoints, censoring is an intrinsic part of the analysis rather than ordinary missingness. The interpretation of Kaplan-Meier and hazard-ratio methods depends on the assumptions governing censoring and the adequacy of the time-to-event model. The ClinicalTrials.gov record does not provide individual-level follow-up information with which to evaluate those assumptions empirically.
For ORR, the registry specifies radiologic assessment every 8 weeks after randomization until disease progression or discontinuation and response determined by Investigator per RECIST 1.1. It does not provide an additional imputation rule in the ClinicalTrials.gov record.
20. Safety and Efficacy Use Different Statistical Questions
The efficacy analysis asks about randomized treatment assignment and clinical time-to-event outcomes. The serious-adverse-event summary instead reports affected subjects over subjects at risk. These are related components of the evidence but should not be collapsed into a single numerical treatment-effect measure.
Efficacy
OS and PFS were analyzed using randomized treatment groups and time-to-event methods, with ITT-based populations specified in the registry data.
Response
ORR was analyzed as a binary outcome using the Cochran-Mantel-Haenszel test in the ITT population.
Safety
Serious adverse events are reported as 232/467 for cabozantinib and 87/237 for placebo.
Interpretation
Each endpoint requires its own denominator, outcome definition, analysis population, and statistical method.
21. Limitations
- Summary-level data: the ClinicalTrials.gov recordset provides selected estimates and P-values rather than the individual-level event and censoring data needed to reproduce the full survival analyses.
- No survival medians reported: the ClinicalTrials.gov record does not provide median OS or median PFS estimates, so none are reported here.
- No Kaplan-Meier reconstruction: individual event and censoring times are not available in the ClinicalTrials.gov record, so a valid Kaplan-Meier curve cannot be reconstructed.
- Limited ORR reporting: the ClinicalTrials.gov record provides the ORR analysis method and P-value but do not provide response proportions or a confidence interval.
- Interim-analysis context: the OS result came from a second planned interim analysis at approximately the 75% information fraction, so the inferential framework should be considered in that context.
- Incomplete multiplicity details: the ClinicalTrials.gov record does not specify the complete alpha-allocation or multiplicity procedure for all posted analyses.
- Incomplete missing-data details: the ClinicalTrials.gov recordset does not provide the full missing-data or imputation strategy.
- Proportional-hazards assumption: the registry-reported summary statistics cannot establish whether the hazard-ratio model is an adequate description throughout follow-up.
- Safety denominator: serious adverse events are reported using 467 subjects at risk in the cabozantinib group and 237 in the placebo group, which differs from the randomized cabozantinib total of 470.
- Subgroup information: the ClinicalTrials.gov recordset does not provide subgroup efficacy estimates, so no subgroup conclusions are drawn.
22. Why This Trial Matters Statistically
CELESTIAL is a useful statistical teaching case because it combines randomized treatment allocation, quadruple masking, an event-driven primary endpoint, a planned interim analysis, stratified survival testing, hazard-ratio estimation, an ITT efficacy population, and a categorical response endpoint analyzed with a different statistical method.
| Concept | How it appears in CELESTIAL |
|---|---|
| Randomization | 707 subjects randomized to cabozantinib or placebo. |
| Quadruple masking | The trial was registered as quadruple-masked. |
| ITT analysis | OS and ORR analyses explicitly used the ITT population. |
| Time-to-event analysis | OS was the primary endpoint and PFS was a secondary endpoint. |
| Log-rank testing | OS and PFS were analyzed with stratified log-rank tests. |
| Hazard ratio | HR 0.76 for OS and HR 0.44 for PFS. |
| Confidence intervals | Two-sided 95% CIs were reported for both hazard ratios. |
| Stratified analysis | OS and PFS analyses incorporated disease etiology, geographic region, and extrahepatic spread and/or macrovascular invasion. |
| Interim analysis | OS was analyzed at a second planned interim analysis at approximately the 75% information fraction. |
| Categorical analysis | ORR was evaluated using the Cochran-Mantel-Haenszel test. |
| Safety denominators | Serious adverse events are reported using affected/at-risk counts rather than the same denominator used for all efficacy analyses. |
The most important statistical lesson is that the treatment effect cannot be separated from the structure of the analysis. A hazard ratio of 0.76 has meaning only when the reader also knows that it is an OS comparison, that the analysis was performed in the ITT population, that the log-rank test was stratified, and that the reported result came from a planned interim analysis.
23. Statistical Methods Explained: Reading the Results Together
Effect size
The OS HR of 0.76 and PFS HR of 0.44 quantify relative differences in event hazards between randomized groups.
Precision
The 95% CIs show how precisely the corresponding hazard ratios are estimated under the statistical framework.
Evidence
The P-values quantify evidence against the relevant null hypotheses but do not measure the magnitude of the effects.
Design context
The OS result was obtained at a planned interim analysis, making the timing of the analysis part of the statistical interpretation.
These four components should be read together. Looking only at the P-value loses information about magnitude and precision. Looking only at the hazard ratio loses information about uncertainty. Looking at either without the endpoint definition and analysis population risks attaching the statistic to the wrong clinical question.
24. Related Tutorials
Learn more about the methods used in this trial:
25. Related Calculators
26. Sources
- ClinicalTrials.gov: CELESTIAL, NCT01908426.
- PubMed record: PMID 35487183.
- PubMed record: PMID 35397508.
- PubMed record: PMID 34621044.
- PubMed record: PMID 33822328.
- PubMed record: PMID 32847838.
The quantitative trial statements on this page are restricted to the registry-reported CELESTIAL ClinicalTrials.gov data. The PubMed links are provided as source records associated with the trial; no additional numerical results from those publications are incorporated into this analysis.
Continue through the Clinical Biostats statistical learning pathway
Use the trial's endpoints and methods as a starting point for deeper study of survival analysis, stratified testing, confidence intervals, and clinical-trial methodology.
27. Record Summary
CELESTIAL provides a compact example of how a randomized phase 3 oncology trial can combine several statistical frameworks. The primary endpoint was overall survival, defined as time from randomization to death from any cause, and analyzed in the ITT population at a second planned interim analysis. The reported OS hazard ratio was 0.76 with a two-sided 95% CI of 0.63–0.92 and P = 0.0049. PFS was analyzed as a secondary time-to-event endpoint with HR 0.44, 95% CI 0.36–0.52, and P < 0.0001. ORR was analyzed using the Cochran-Mantel-Haenszel test, with P = 0.0086.
The statistical interpretation depends on more than those numbers. The analysis populations, stratification factors, interim-analysis timing, endpoint definitions, and distinction between time-to-event and binary outcomes determine what each statistic actually means. The serious-adverse-event data likewise require their own denominators and should not be treated as an efficacy comparison.