A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant (The AETHERA Trial): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant (The AETHERA Trial) (NCT01100502), a randomized phase 3 study. The primary outcome is Progression-free Survival by Independent Review.

2. Clinical Question

The clinical question concerns outcomes after transplant in a population selected for high risk of residual Hodgkin lymphoma. The endpoint combines disease progression, as documented by independent review, with death from any cause. The event is whichever of these occurs first after randomization. This is a time-to-event question: it concerns both whether an event occurs and how long participants remain without a recorded event during follow-up.

The intervention was not compared with no care. Both arms included best supportive care, and the comparison was brentuximab vedotin versus placebo. The study's brief summary describes the aim as evaluating efficacy and safety, but the primary result described in the registry is progression-free survival. Overall survival, adverse events or laboratory abnormalities, and anti-therapeutic antibodies to brentuximab vedotin are listed as secondary outcomes. Numerical results for those outcomes are not included in the record.

The randomized design supports comparing assigned groups, while the intention-to-treat analysis set identifies the population used for the primary endpoint. The registry record does not report further detail about eligibility criteria, the methods used to determine high risk, or the specific procedures for independent review. Those details therefore cannot be inferred from the outcome summary. The posted endpoint result is a group-level statistical comparison, not a prediction for an individual participant.

3. Trial Design

AETHERA is recorded as a completed phase 3, randomized, parallel-group study with 329 participants enrolled. The title and brief description characterize it as double-blind and placebo-controlled; the masking field records quadruple masking. The registry record identifies the study as multicenter. It compares brentuximab vedotin plus best supportive care with placebo plus best supportive care in patients at high risk of residual Hodgkin lymphoma following autologous stem cell transplant.

The brentuximab vedotin regimen is listed as 1.8 mg/kg by intravenous infusion every 3 weeks. Placebo was also administered by intravenous infusion every 3 weeks. The registry does not identify which groups of people were included in the quadruple masking designation, so the masking label should not be expanded into assumptions about who knew treatment assignments. The method used to generate the random allocation sequence and the process for concealing assignments are not reported in the registry record.

The primary outcome was progression-free survival by independent review, analyzed in the intention-to-treat analysis set. The stated timeframe was up to approximately 4 years. The event definition was time from randomization to the first documentation of disease progression by independent review or death due to any cause, whichever came first. The registry reports the median for each arm and a sponsor-reported hazard ratio from a log-rank analysis.

Overall survival, incidence of adverse events or laboratory abnormalities, and incidence of anti-therapeutic antibodies to brentuximab vedotin are listed as secondary outcomes. The record lists four outcome measures, while three secondary outcome categories are named. Numerical secondary-outcome results are not reported in the registry record. The original sample-size justification, its target event count, any interim analyses, and the full statistical analysis plan are also not reported. The planning illustrations associated with the observed result should not be mistaken for the trial's original design calculations.

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: Intention-to-Treat 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.

Population: Intention-to-Treat analysis set

6. Primary Endpoint

The registry lists the primary outcome as Progression-free Survival by Independent Review, measured over Up to approximately 4 years.

Progression-free survival measures the time from randomization until the first qualifying event. In this trial, a qualifying event was disease progression documented by independent review or death from any cause, whichever happened first. Participants without a recorded event contribute information about the time they remained free of a recorded progression or death, subject to the trial's follow-up and analysis procedures.

This type of endpoint is used when the timing of an event matters and when follow-up may differ among participants. General statistical explanation: time-to-event methods can use information from participants who have not had an event by the time their observation ends, rather than treating all such participants as if their outcome were fully known. The procedures used to censor observations and handle missing follow-up in this trial are not reported in the registry record.

Independent review is part of the endpoint definition. It indicates that disease progression was assessed through a review process identified as independent, rather than relying only on an investigator-reported progression label. The specific review procedures and criteria are not reported in the registry record.

The registry reports median progression-free survival of 42.9 months for brentuximab vedotin and 24.1 months for placebo. These medians describe the time point at which the estimated event-free survival distribution reaches its midpoint, under the analysis used. They do not describe each participant's experience, and they do not by themselves summarize the full pattern of event timing. The hazard ratio provides a separate comparison over follow-up. Interpretation of both measures depends on the endpoint definition, follow-up, and analysis methods.

7. Results Posted in the Registry

• Brentuximab Vedotin vs Placebo: hazard ratio 0.57 (95% CI 0.40–0.81), reported p = 0.001 (as reported in the registry).

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a time-to-event measure, and its reported comparison uses a hazard ratio from a log-rank analysis. General statistical explanation: time-to-event analysis is designed for outcomes where both the occurrence and timing of an event matter. Participants may have different lengths of follow-up, and some may not have experienced the event by the end of their recorded observation. The analysis can incorporate time observed without an event, subject to assumptions and the handling of censoring.

What does the hazard ratio describe?

A hazard is the instantaneous rate of an event at a point in time among people still at risk at that time. A hazard ratio compares that rate between groups. The registry reports a hazard ratio of 0.57 for brentuximab vedotin versus placebo, with a 95% confidence interval from 0.40 to 0.81. General statistical explanation: this is a relative comparison of event hazards, not a direct comparison of the proportion of participants who ever experience progression or death. Nor is it the same quantity as the ratio between the two reported medians.

The interpretation of a single hazard ratio is clearest when the relative hazards are reasonably stable over time. Whether that condition was assessed, and what diagnostics or alternative approaches might have been used, are not reported in the registry record. The hazard ratio should therefore be read as the sponsor-reported summary from the stated analysis, not as proof of a particular hazard pattern throughout follow-up.

What does the log-rank method contribute?

The log-rank method is a general statistical procedure for comparing time-to-event experience between groups. It uses the ordering of event times and the participants at risk over follow-up. The registry identifies the log-rank method for the reported comparison and gives a p-value of 0.001. General statistical explanation: the test assesses whether the observed group patterns are compatible with a null hypothesis of no difference in event-time experience, under the method's assumptions. It does not quantify the size of the difference by itself; the hazard ratio and confidence interval provide an estimate and a measure of its uncertainty.

The record does not report whether the log-rank test was stratified, which factors might have been used for stratification, or whether the hazard ratio came from a particular regression model. It does not provide standard errors, the number of events in the primary analysis, or details of the event-time curves. Those omissions limit independent assessment of the analysis implementation. They do not alter the fact that the registry identifies the sponsor's reported method and result.

How should medians and confidence intervals be read?

The reported median progression-free survival values are 42.9 months for brentuximab vedotin and 24.1 months for placebo. A median is the point in the estimated event-time distribution by which half of the group is estimated to have had an event, under the analysis used. It is not a mean, and it does not imply that every participant's time to progression or death was close to that value. The confidence interval for the brentuximab vedotin median is reported from 30.4 to 42.9 months. The placebo median has a lower confidence limit of 11.5 months, while its upper limit is not reported in the registry record.

General statistical explanation: confidence intervals express uncertainty in an estimate under a statistical procedure. They are not a range containing a specified proportion of individual participants' outcomes. A confidence interval for a median and a confidence interval for a hazard ratio concern different parameters and should not be compared as if they were interchangeable. The hazard-ratio interval is the registry's direct interval for the relative group comparison.

Why does over-dispersion matter in some analyses?

General statistical explanation: over-dispersion occurs when observed variation is larger than a model's assumed variation. In count or rate analyses, ignoring it can make uncertainty estimates too small and tests too optimistic. This primary outcome is a time-to-event endpoint, and the registry identifies a log-rank analysis and hazard ratio rather than a count model. No over-dispersion assessment is reported, and there is no basis in the registry record to say that over-dispersion was relevant to the primary analysis.

What can be said about the analysis population?

The primary analysis population is named as the intention-to-treat analysis set. General statistical explanation: an intention-to-treat approach is ordinarily intended to preserve comparison according to randomized assignment, rather than redefining groups according to treatment received. The precise operational definition used in this trial, including any exclusions from the analysis set, is not reported in the registry record. The primary-outcome arm counts are 165 and 164, but these counts alone do not reveal the amount of missing follow-up or the number of events analyzed.

The registry lists overall survival, incidence of adverse events or laboratory abnormalities, and incidence of anti-therapeutic antibodies to brentuximab vedotin as secondary outcomes. It does not provide numerical results for those outcomes in the record summarized. It also does not report whether multiplicity adjustments were used across outcomes, how missing data were handled, whether there were interim analyses, or the full analysis plan. Those methods should not be assumed from the primary result or from the study's phase designation.

10. Confidence Intervals and Precision

The principal comparison is reported as a hazard ratio of 0.57, with a 95% confidence interval from 0.40 to 0.81. The interval stays below 1, the value representing equal hazards in the ratio interpretation. General statistical explanation: a confidence interval communicates the range of relative hazard values that remain compatible with the observed data and the method's assumptions at the stated confidence level. It conveys uncertainty around the estimate, rather than certainty that the true value lies within the particular displayed endpoints.

The interval is informative about precision as well as direction. It excludes 1 under the reported interval calculation, but it still includes a range of possible relative hazard values. The registry does not provide enough detail to assess alternative intervals, model diagnostics, or sensitivity to analysis choices. The reported p-value is 0.001, but the p-value and interval serve distinct purposes: one summarizes evidence against a null hypothesis under a test, while the other communicates uncertainty in the estimated hazard ratio.

The medians have their own uncertainty. For brentuximab vedotin, the median is 42.9 months, with a confidence interval from 30.4 to 42.9 months. For placebo, the median is 24.1 months and the lower confidence limit is 11.5 months; the upper limit is not reported in the registry record. The intervals for arm-specific medians should not replace the interval for the hazard ratio when describing the group comparison. The registry does not report confidence intervals for every other statistic mentioned in the record.

General statistical explanation: precision depends on the information available for estimating an outcome, including the number and timing of events and the length and completeness of follow-up. The total enrollment is 329, but enrollment alone does not determine precision for a time-to-event result. The record does not give the total primary endpoint events or detailed follow-up distribution, so those features cannot be evaluated from the posted summary. The interval provides the clearest reported measure of uncertainty for the relative hazard comparison.

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 planning illustrations are based on the observed hazard-ratio effect, not on the trial's original design assumptions. For time-to-event outcomes, the listed sample-size quantities are total events, not participants per arm. They show total event targets under alternative planning scenarios: using 100% of the observed effect, 100 events for 80% power and 134 events for 90% power; using 75% of the observed effect, 177 events for 80% power and 237 events for 90% power; and using 50% of the observed effect, 398 events for 80% power and 533 events for 90% power.

General statistical explanation: power is the probability that a planned analysis will reject a specified null hypothesis if a particular effect is truly present, under the assumptions used for planning. The 80% power column describes event targets for a design intended to have an 80% chance of detecting the stated effect; the 90% column describes targets for a design intended to have a 90% chance. These are design probabilities, not guarantees about a result. The total event targets are not a count of participants in either treatment arm.

The planning assumptions listed are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The event calculations use the Schoenfeld method. The trial's original sample-size justification and design assumptions are not reported in the registry record. The actual primary-outcome allocation was 165 and 164, while the planning calculation assumes equal allocation.

Smaller effects require more events to detect at the same stated power in these planning scenarios. The displayed sample-size figures are planning illustrations only; this is not observed power. The planning scenarios do not establish what the trial was originally designed to detect, and event targets cannot be treated as participant targets without additional assumptions about follow-up and event occurrence.

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

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.570, so ln(HR) = -0.5621.
2. d = 4 × (1.96 + 0.842)² / [ln(0.570)]² = 99.4, rounded up to 100 events in total 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
hr <- 0.57                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(1100502)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 100 (80% power), 134 (90% power)
 75% of observed effect: events = 177 (80% power), 237 (90% power)
 50% of observed effect: events = 398 (80% power), 533 (90% power)
Simulated power with 100 events: 0.804 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

13. Group-Sequential Design Analysis

Many time-to-event trials, especially in oncology, stop or report early when interim data are overwhelming, so a single fixed-sample number understates the real design problem. The calculation below is an illustrative group-sequential design built from this trial's posted control median and hazard ratio. The registry record does not state the planned number of looks or the spending function, so the design is a planning illustration, not a reconstruction of the protocol. Assumed: one-sided α = 0.025, 90% power, three equally spaced looks on information, Lan-DeMets O'Brien-Fleming spending, 24 months of accrual, 60 months in total and a 1% monthly dropout hazard.

Under these assumptions the design needs about 253 participants in total, with the boundaries below.

Fixed design versus group-sequential alternatives

Group-sequential designs cost a small increase in maximum sample size and events compared with the fixed design, in exchange for the chance to stop early for overwhelming efficacy. O'Brien-Fleming spending keeps early boundaries very conservative and the final boundary close to the fixed-design value, whereas Pocock spending spends more alpha early.

Sensitivity to a smaller true effect

Planning for exactly the observed effect is optimistic, because observed effects in published trials tend to be somewhat larger than the true effect. The table repeats the main design (three looks, O'Brien-Fleming spending, 90% power) for smaller true hazard ratios.

For context, this trial enrolled 329 participants.

Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993. Agreement between the two packages confirms the boundary calculation.

R code and output

suppressWarnings(suppressMessages({ library(gsDesign); library(rpact) }))
med_control <- 24.1          # control-arm median, months (converted from the posted unit)
hr          <- 0.57          # hazard ratio used for planning
lambdaC     <- log(2) / med_control
eta         <- 0.01               # dropout hazard per month (assumption)
acc_months  <- 24                 # accrual duration (assumption)
study_months<- 60                 # total study duration (assumption)

design <- function(k, sfu, beta, h = hr) gsSurv(k = k, test.type = 1, alpha = 0.025, beta = beta, sfu = sfu,
  lambdaC = lambdaC, hr = h, hr0 = 1, eta = eta, gamma = 1, R = acc_months, T = study_months, minfup = study_months - acc_months)

# Main design: 3 looks, Lan-DeMets O'Brien-Fleming spending, one-sided alpha 0.025, 90% power
x <- design(3, sfLDOF, 0.10)
cat(sprintf("N_TOTAL|%s\n", format(ceiling(sum(x$gamma * x$R)), big.mark = ",")))
for (i in 1:3) cat(sprintf("GS|%d|%.1f|%.0f|%.3f|%.5f|%.5f\n", i, x$T[i], x$n.I[i], x$upper$bound[i], pnorm(-x$upper$bound[i]), cumsum(x$upper$spend)[i]))
cat("\n"); print(gsBoundSummary(x))

# Comparison of designs
cmp <- list(list("Fixed design, one analysis", 1, sfLDOF), list("Two looks, O'Brien-Fleming", 2, sfLDOF),
            list("Three looks, O'Brien-Fleming", 3, sfLDOF), list("Three looks, Pocock", 3, sfLDPocock))
cat("\n")
for (b in c(0.20, 0.10)) for (d in cmp) {
  y <- design(d[[2]], d[[3]], b)
  cat(sprintf("DES|%s|%d|%.0f|%s|%.1f\n", d[[1]], round(100 * (1 - b)), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ","), tail(y$T, 1)))
}

# Sensitivity: what if the true effect is smaller than the observed one? (3 looks, O'Brien-Fleming, 90% power)
cat("\n")
for (fr in c(1, 0.75, 0.5)) {
  y <- design(3, sfLDOF, 0.10, exp(log(hr) * fr))
  cat(sprintf("SENS|%.2f|%.3f|%.0f|%s\n", fr, exp(log(hr) * fr), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ",")))
}

# Independent cross-check of the boundaries with rpact
r <- getDesignGroupSequential(kMax = 3, alpha = 0.025, beta = 0.10, sided = 1, typeOfDesign = "asOF", informationRates = x$timing)
cat(sprintf("\nCross-check, upper boundaries: gsDesign %s | rpact %s\n", paste(round(x$upper$bound, 3), collapse = ", "), paste(round(r$criticalValues, 3), collapse = ", ")))

Method: LachinFoulkes 
    Analysis               Value Efficacy
   IA 1: 33%                   Z   3.7103
      N: 230         p (1-sided)   0.0001
  Events: 45        ~HR at bound   0.3300
   Month: 22    P(Cross) if HR=1   0.0001
             P(Cross) if HR=0.57   0.0338
   IA 2: 67%                   Z   2.5114
      N: 254         p (1-sided)   0.0060
  Events: 90        ~HR at bound   0.5882
   Month: 35    P(Cross) if HR=1   0.0060
             P(Cross) if HR=0.57   0.5603
       Final                   Z   1.9930
      N: 254         p (1-sided)   0.0231
 Events: 135        ~HR at bound   0.7091
   Month: 60    P(Cross) if HR=1   0.0250
             P(Cross) if HR=0.57   0.9000



Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993

14. Analyses Reported by the Sponsor

The sponsor's own primary analysis is reported as a log-rank comparison with a hazard ratio of 0.57, a 95% confidence interval from 0.40 to 0.81, and p = 0.001. The arm-specific median progression-free survival values are 42.9 months for brentuximab vedotin and 24.1 months for placebo. The registry record identifies the hazard ratio and test as sponsor-reported results.

The accompanying planning illustrations are calculations based on the observed effect and stated assumptions. They are not an independent replacement for the sponsor's analysis, do not change the reported endpoint estimate, and do not establish the original design assumptions. No discrepancy between the sponsor-reported result and the posted comparison is identified in the registry record. Accordingly, interpretation should center on the sponsor's reported hazard ratio, interval, and log-rank p-value rather than treating a planning calculation as a second analysis of the trial outcome.

General statistical explanation: a recalculation from summary information, when available, may not reproduce a trial's full analysis because it may omit participant-level event timing, censoring, stratification, or model details. The registry record does not report such additional details for independent reconstruction. The reported analysis therefore remains the relevant account of the trial's primary comparison, with its uncertainty and reporting limits made explicit.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome: progression-free survival by independent review. It also lists secondary outcomes for overall survival, adverse events or laboratory abnormalities, and anti-therapeutic antibodies to brentuximab vedotin. The record lists four outcome measures in total, but numerical results for the secondary outcomes are not reported in the registry record.

Multiplicity arises when multiple outcomes, comparisons, time points, or subgroups are tested. General statistical explanation: making many statistical tests can increase the chance of at least one result appearing notable by chance if no adjustment or other control is used. Whether multiplicity adjustments were planned or used in this trial is not reported in the registry record. The listed p-value should therefore be understood as the reported primary comparison result; the available record does not establish how any family of secondary tests was controlled.

The primary analysis population is described as the intention-to-treat analysis set. The registry does not provide its detailed definition, including the handling of participants who withdrew, did not receive assigned treatment, or lacked endpoint assessments. It does not report the censoring rules, the amount of missing follow-up, or sensitivity analyses addressing missing data. General statistical explanation: time-to-event analyses commonly distinguish a participant whose observation ends without a recorded event from one who is known to remain event-free indefinitely. The reliability of such analyses depends on the follow-up and censoring assumptions; the record does not provide enough information to evaluate those assumptions.

The number and timing of interim analyses are not reported in the registry record. Neither the stopping rules nor any adjustment for interim testing are reported. The full statistical analysis plan, the original sample-size justification, subgroup-analysis plans, and details of any stratification are also not reported. These are limits on reconstructing the analysis and evaluating how all statistical decisions were made; they should not be filled in by assumption.

The stated primary endpoint timeframe is up to approximately 4 years. That description does not provide a median follow-up duration or a complete account of observation time. The record reports an intention-to-treat primary population but does not explain the difference between the primary outcome arm counts and the adverse-event group counts. These omissions do not negate the posted result, but they constrain assessment of missingness, analysis populations, and the broader evidence across outcomes.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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: pneumonia (4.2%), pyrexia (3.6%), vomiting (3.0%), nausea (2.4%), hepatotoxicity (1.8%).

The registry reports serious adverse events among 21 of 160 participants at risk in the placebo group and 43 of 167 participants at risk in the brentuximab vedotin group. Other adverse events are reported among 127 of 160 at risk in the placebo group and 151 of 167 at risk in the brentuximab vedotin group. Death counts are listed as 40 and 45, respectively. The record does not state in this summary that these deaths were caused by treatment, and the counts should not be interpreted as treatment-related deaths.

The listed serious adverse-event terms and percentages are pneumonia, 4.2%; pyrexia, 3.6%; vomiting, 3.0%; nausea, 2.4%; hepatotoxicity, 1.8%; and peripheral sensory neuropathy, 1.8%. The record does not provide event-specific denominators or further detail about timing, severity grading, relatedness, or overlap between participants in this listing. These percentages should therefore be read as the registry's reported values, not as independently reconstructed risks.

The adverse-event group counts differ from the primary outcome group counts. The reason for this difference is not reported in the registry record. These aggregate safety figures do not establish causation, account for differences in observation time, or capture the full clinical context of each event. The registry lists adverse events or laboratory abnormalities as a secondary outcome, but a complete set of numerical secondary-outcome results is not included in the record.

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

The registry's primary result is a comparison of progression-free survival after autologous stem cell transplant among participants considered at high risk of residual Hodgkin lymphoma. The reported median was 42.9 months in the brentuximab vedotin group and 24.1 months in the placebo group. The sponsor-reported hazard ratio was 0.57, with a 95% confidence interval from 0.40 to 0.81 and a log-rank p-value of 0.001. These values describe the posted analysis of the specified endpoint.

General statistical explanation: the hazard ratio summarizes relative event hazards over follow-up under the analysis used. It does not state the absolute probability that a particular participant will experience progression or death, and it does not mean the same relative comparison applies at every time point. The median is a distributional summary, not an expected individual outcome. The confidence interval indicates uncertainty in the hazard-ratio estimate; it does not eliminate uncertainty about the underlying effect or about how results apply outside the studied population.

The endpoint combines independently reviewed disease progression with death from any cause. It is not identical to overall survival, which is listed separately as a secondary outcome. Numerical results for overall survival, the other listed secondary outcomes, and the detailed safety outcomes are not reported in the registry record. The primary result consequently cannot stand in for the complete set of trial outcomes.

The data do not establish that every participant in one group had a better outcome than every participant in the other group. Nor do they show the reasons for particular participants' events, the effect of treatment on an individual, or how outcomes might differ across subgroups. The registry record does not report subgroup results, missing-data sensitivity analyses, or a detailed account of the endpoint assessment process beyond independent review.

The result should be read as a statistical comparison from a randomized trial with a defined population, treatment comparison, endpoint, and analysis. Its interpretation is bounded by the information reported: the confidence interval, the stated log-rank method, the intention-to-treat population, and the absence of further analysis details in the registry record. The reported p-value is evidence from a test, not proof of a particular clinical consequence or a measure of the result's practical importance.

18. Why This Trial Matters Statistically

Statistically, this trial illustrates why time-to-event results are often communicated with more than one measure. The arm-specific medians describe estimated event-free time points, while the hazard ratio summarizes the relative event hazard and the confidence interval expresses uncertainty in that comparison. The log-rank p-value adds a test result, but it does not replace the estimate or its interval. Reading these measures together helps distinguish the magnitude of the reported comparison from the strength and precision of the statistical evidence.

The endpoint also makes the event definition central to interpretation. Progression-free survival in this record includes independently reviewed disease progression or death from any cause, whichever comes first. That composite definition is clinically and statistically different from overall survival, another outcome listed by the registry. A reader cannot assume that the primary result answers the secondary-outcome questions, particularly because numerical secondary results are not reported in the registry record.

The study's randomized, placebo-controlled, parallel-group design provides a structured basis for comparing assigned groups, and the primary result uses an intention-to-treat analysis set. At the same time, the registry leaves several important methods details unreported, including missing-data handling, interim analyses, multiplicity procedures, and the original sample-size justification. This distinction matters: a clearly reported result can be interpreted while remaining cautious about aspects of the analysis that cannot be independently assessed from the registry entry.

The planning illustrations also demonstrate the difference between a trial result and a design scenario. Their event targets vary according to the assumed fraction of the observed effect and stated power level. They do not describe observed power or establish what the original trial planned. Keeping that distinction clear prevents planning calculations from being mistaken for evidence about the actual outcome.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives a concise account of the primary result but not the full analysis documentation. It identifies the log-rank method, hazard ratio, confidence interval, p-value, median values, and intention-to-treat population. It does not report the complete statistical analysis plan, original sample-size justification, interim analyses, multiplicity procedures, detailed censoring rules, or missing-data methods. These omissions limit independent evaluation of the full analysis strategy and its sensitivity to assumptions.

The primary endpoint is described as progression-free survival by independent review, but the specific progression criteria and independent-review procedures are not reported in the registry record. The record also does not describe whether the hazard-ratio analysis was stratified or whether proportional hazards were assessed. The interpretation of a single hazard ratio depends in part on how the relative hazards behave over time, and that assessment cannot be reconstructed from the summary alone.

The registry states that the endpoint timeframe was up to approximately 4 years, but it does not report a median follow-up duration or the total number and timing of primary endpoint events. Those details would help readers assess the information contributing to the time-to-event estimate. The arm-specific median confidence interval for placebo has a lower limit of 11.5 months, while an upper limit is not reported in the registry record.

The registry lists three secondary outcome categories and four outcome measures in total, but numerical secondary-outcome results are not included in the record. The adverse-event summary gives at-risk and affected counts and a list of serious adverse-event terms, but it does not provide detailed event timing, severity grades, relatedness assessments, or explanations for the different group counts across outcomes. These limits prevent a complete interpretation of secondary efficacy and safety outcomes from this record alone.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant (The AETHERA Trial) — NCT01100502.
• Registry record last updated 2021-05-14; status last verified 2021-04.
• Results first posted 2015-11-11.
• 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.

23. Record Summary

The registry record describes AETHERA, a completed randomized, double-blind, placebo-controlled, multicenter phase 3 trial with 329 participants. It compared brentuximab vedotin plus best supportive care with placebo plus best supportive care after autologous stem cell transplant among people at high risk of residual Hodgkin lymphoma.

The primary outcome was independently reviewed progression-free survival in the intention-to-treat analysis set, measured from randomization to progression or death from any cause. Reported median values were 42.9 months and 24.1 months. The sponsor-reported hazard ratio was 0.57, with a 95% confidence interval from 0.40 to 0.81 and p = 0.001 by log-rank analysis.

The registry lists overall survival, adverse events or laboratory abnormalities, and anti-therapeutic antibodies as secondary outcomes. The original design justification, detailed missing-data methods, multiplicity procedures, and interim-analysis information are not reported in the registry record. The result should therefore be interpreted as the reported primary time-to-event comparison, with its stated uncertainty and reporting limits.