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 results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma. (NCT01035229), a randomized phase 3 study. The primary outcome is Overall Survival (OS).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01035229 |
| Phase | Phase 3 |
| Condition | Carcinoma |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 546 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Adults with advanced hepatocellular carcinoma whose disease progressed while on or after sorafenib treatment, or who were intolerant to sorafenib. The primary analysis population was the Full Analysis Set, defined as all randomized patients.
Intervention
Everolimus, also called RAD001 in the registry record, taken as a daily oral dose of 7.5 mg, together with best supportive care according to local practice.
Comparator
Placebo plus best supportive care according to local practice.
Primary question
How did overall survival, measured from randomization to death from any cause, compare between the everolimus-plus-BSC and placebo-plus-BSC groups?
The study was designed for a setting in which patients had advanced hepatocellular carcinoma after sorafenib treatment had failed or could not be tolerated. It compared adding everolimus with adding placebo while both groups received best supportive care. This makes the central question a comparison of the assigned study treatments on top of supportive care, rather than a comparison of supportive care with no care.
The registry identifies overall survival as the primary outcome. It also lists time to tumor progression, disease control rate, performance status, quality-of-life scores and pharmacokinetic assessments among the secondary outcomes. Those measures concern different aspects of the trial: survival, tumor status, patient-reported or functional outcomes, and drug concentration. They do not replace the primary question about time to death.
3. Trial Design
EVOLVE-1 was a randomized, phase III, double-blind, placebo-controlled, multicenter, parallel-group study sponsored by Novartis Pharmaceuticals. The registry lists enrollment as 546 and the study status as completed. The recorded start is 2010-04 and primary completion is 2013-10.
Patients were assigned to everolimus plus best supportive care or placebo plus best supportive care. The registry describes assignment in a 2:1 ratio. The everolimus arm is described as receiving a daily oral dose of 7.5 mg, with best supportive care delivered according to local practice. The comparator received placebo plus best supportive care. The posted arm sizes are 362.0 for everolimus plus BSC and 184.0 for placebo plus BSC.
Randomization is intended to make treatment groups comparable, on average, with respect to factors that might affect outcomes. Double masking is intended to limit the influence of treatment knowledge on care and outcome assessment. The registry record does not report the specific masking procedures, the randomization method, or any stratification factors. The title identifies the study as the EVOLVE-1 study.
The primary outcome was overall survival, defined as the time from randomization to death from any cause. The stated analysis time point was when 454 OS events were observed. The registry describes a stratified log-rank test at a one-sided 2.5% level of significance for the comparison. It does not identify the strata in the record.
Secondary outcomes include disease control rate and pharmacokinetic measurements, as well as measures of tumor progression, performance status and quality of life. The registry record includes some secondary outcome results, but not a complete set of results for every listed outcome. Details such as the handling of missing observations and the full analysis procedures 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
| Stage | Everolimus + Best Supportive Care (BSC) | Placebo + Best Supportive Care |
|---|---|---|
| STARTED | 362 | 184 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 362 | 184 |
Reasons for not completing this period:
| Reason | Everolimus + Best Supportive Care (BSC) | Placebo + Best Supportive Care |
|---|---|---|
| Adverse Event | 61 | 14 |
| Withdrawal by Subject | 20 | 7 |
| Lost to Follow-up | 1 | 0 |
| Administrative problems | 1 | 1 |
| Death | 13 | 5 |
| New cancer therapy | 2 | 0 |
| Protocol Violation | 0 | 2 |
| Sponsor's decision to end study | 3 | 3 |
| Disease Progression | 261 | 152 |
Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) comprised all randomized patients.
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.
| Characteristic | Unit | Everolimus + Best Supportive Care (BSC) | Placebo + Best Supportive Care | Total |
|---|---|---|---|---|
| Participants analysed | 362 | 184 | 546 | |
| Age, Continuous | Years | 65.1 (SD 11.70) | 64.2 (SD 10.41) | 64.8 (SD 11.28) |
| Age, Customized: < 35 years | Participants | 7 | 1 | 8 |
| Age, Customized: >=35 - <55 years | Participants | 48 | 31 | 79 |
| Age, Customized: >=55 - <65 years | Participants | 100 | 61 | 161 |
| Age, Customized: >= 65 years | Participants | 207 | 91 | 298 |
| Sex: Female, Male: Female | Participants | 59 | 24 | 83 |
| Sex: Female, Male: Male | Participants | 303 | 160 | 463 |
| Race/Ethnicity, Customized: Caucasian | Participants | 192 | 110 | 302 |
| Race/Ethnicity, Customized: Black | Participants | 6 | 3 | 9 |
| Race/Ethnicity, Customized: Asian | Participants | 137 | 58 | 195 |
| Race/Ethnicity, Customized: Pacific Islander | Participants | 0 | 1 | 1 |
| Race/Ethnicity, Customized: Other | Participants | 27 | 12 | 39 |
| Weight | kg | 69.6 (SD 15.62) | 71.3 (SD 17.71) | 70.2 (SD 16.35) |
| Height | cm | 167.9 (SD 8.66) | 169.2 (SD 8.84) | 168.3 (SD 8.73) |
| BMI | kg/m^2 | 24.5 (SD 4.64) | 24.8 (SD 4.99) | 24.6 (SD 4.76) |
6. Primary Endpoint
The registry lists the primary outcome as Overall Survival (OS), measured over When 454 OS events were observed.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | Months |
| Endpoint classification | Time-to-Event Analysis |
Overall survival measures the time from randomization until death from any cause. It is used as an endpoint because it captures survival regardless of the specific cause of death and does not depend on a judgment about whether a particular event represents tumor progression. In this study, the registry defines the outcome in those terms and specifies the Full Analysis Set as all randomized patients.
The posted arm results give median overall survival in months, with a 95% confidence interval for each median. The median is the time by which half of the analyzed group has experienced the event, under the survival-analysis definition; it is not the average survival time and does not describe the experience of every participant. A confidence interval conveys uncertainty around the estimated median. It is not an interval containing the survival times of most individual participants.
Overall survival is a time-to-event outcome. Its analysis can use information about the timing of deaths while accounting for participants whose event time is not observed during the analysis period. The registry record does not report details of censoring or the specific handling of incomplete follow-up. It states that the comparison was to use a stratified log-rank test, but it does not post a hazard ratio, a confidence interval for a treatment contrast, or a p-value for that primary comparison.
The record states that the primary analysis time point was when 454 OS events were observed. That event-based timing describes when the analysis was planned or conducted; it does not supply the missing comparative estimate. The arm medians alone should therefore be read as descriptive summaries, not as a complete report of the trial's primary treatment comparison.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
Median overall survival was 7.56 months in the everolimus-plus-BSC group, with a 95% confidence interval from 6.7 to 8.74 months. In the placebo-plus-BSC group, median overall survival was 7.33 months, with a 95% confidence interval from 6.28 to 8.74 months. These are arm-specific estimates. The registry record does not post the sponsor's comparative hazard ratio, its confidence interval, or the result of the specified log-rank test.
The medians are close in the posted summaries, but a comparison of medians is not a substitute for the planned time-to-event analysis. The medians do not show how the survival experience differed over the full follow-up period, and the arm-specific confidence intervals do not provide a confidence interval for the treatment contrast. Their overlap also is not a formal test of the treatment comparison. Without the sponsor-reported comparison result, the registry record does not permit a complete statistical interpretation of the primary endpoint.
The registry describes overall survival as measured from randomization to death from any cause and says the Full Analysis Set included all randomized patients. It also states that the planned comparison used a stratified log-rank test with a one-sided 2.5% significance level. The fact that this method is specified does not establish its result. The number of events at the stated analysis point is given as 454, but the event total alone does not indicate the direction, size, or precision of a treatment effect.
Secondary results address other questions and should be kept distinct from the primary survival comparison. For disease control rate, the posted values are 56.1 for everolimus plus BSC and 45.1 for placebo plus BSC. The unadjusted recalculated risk difference is -0.110 for placebo relative to everolimus, with a 95% confidence interval from -0.198 to -0.021 and p = 0.015. This is an unadjusted secondary comparison, not the reported primary survival analysis.
The pharmacokinetic results compare the posted 7.5mg and 5mg everolimus groups for Cmin and Cmax. These are drug-concentration summaries, not efficacy comparisons between the randomized treatment arms. Their group sizes are markedly different, and the registry record does not report sponsor analyses for these secondary results. These results should not be used to fill the gap in the primary endpoint reporting.
Overall, the registry record gives arm-level primary survival estimates but not the comparative analysis result that would directly answer the trial's main question. A conclusion about the primary treatment contrast cannot be derived from the medians alone.
9. Statistical Methods Explained
What does the median summarize?
Overall survival is a time-to-event outcome: each participant's outcome concerns the time from randomization to death from any cause. The median survival estimate is the point at which the estimated survival experience reaches the halfway mark. It is a summary of the group distribution, not a statement that every participant lived for the median duration. It also is not an arithmetic average.
Time-to-event methods are useful when participants have different lengths of follow-up or when some have not experienced the event by the analysis time. In general, these methods can incorporate the observed follow-up without treating every participant as if the event had occurred. The registry record does not report the censoring rules or details of how incomplete follow-up was handled, so those procedures cannot be assessed from this record.
What do the confidence intervals mean?
The registry posts a 95% confidence interval for each arm's median. In general, a confidence interval describes the uncertainty of an estimate under the statistical procedure used to construct it. It does not give the range of individual participant outcomes, nor does it directly estimate the uncertainty in the difference between arms. The arm-specific intervals are 6.7 to 8.74 months for everolimus plus BSC and 6.28 to 8.74 months for placebo plus BSC.
For a treatment comparison, the relevant interval would be one attached to a comparative measure, such as a hazard ratio or a difference in a defined summary. The primary comparison's estimate and interval are not reported in the registry record. Comparing arm-specific intervals by eye is not equivalent to testing the difference between treatments.
What does the planned log-rank test do?
The registry says the overall-survival comparison was to use a stratified log-rank test at a one-sided 2.5% level of significance. In general, a log-rank test compares the event-time distributions between groups over follow-up, rather than comparing only their medians. Stratification means the comparison accounts for specified strata when forming the test; the registry record does not report which strata were used. The stated significance level describes the planned decision threshold, not the observed p-value. No result for this primary test is posted in the registry record.
The record states that the analysis was to occur when 454 OS events were observed. An event-based analysis time point can be used in time-to-event trials because the information available for the comparison depends in part on the number of events. That statement does not provide the treatment effect estimate or establish that a particular result was statistically significant.
How should the secondary comparisons be read?
Disease control rate is a binary outcome: a participant either meets the stated disease-control definition or does not. The registry posts arm percentages and an unadjusted recalculated risk difference, along with a confidence interval and p-value. A risk difference expresses the contrast on the absolute probability scale. The posted comparison is unadjusted, and the registry does not include a sponsor-reported analysis for it. The recalculated result should therefore be understood as a simple comparison of posted summary data, not as a replacement for a prespecified adjusted analysis.
The reported pharmacokinetic summaries are means with standard deviations. In general, the mean describes the center of observed values, while the standard deviation describes their spread around the mean. The registry gives Cmin results for the 7.5mg and 5mg groups and Cmax results for those groups. The groups are not the randomized everolimus-versus-placebo comparison, so these estimates answer a pharmacokinetic question rather than the trial's primary efficacy question. The registry record does not provide sponsor-reported analyses for these comparisons.
How should planning illustrations be interpreted?
Any sample-size planning illustrations based on observed effects are retrospective planning exercises, not observed power for this completed trial. The registry states that the illustrations use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect set to a stated fraction of the observed effect. They are not the trial's own design calculations. The registry record does not report the protocol's sample-size justification, so the illustrations cannot establish what assumptions guided the original design.
In general, planning estimates depend on the assumed effect and analysis conditions. If an observed effect is used as the planning assumption, the resulting illustration inherits uncertainty from that estimate. Such calculations do not show that the trial had a particular probability of finding an effect, and they do not resolve the absence of the sponsor's primary comparison result.
10. Multiplicity, Missing Data and Analysis Populations
The registry record reports the primary endpoint and names a planned stratified log-rank test at a one-sided 2.5% significance level. It does not report the primary test result or a comparative hazard ratio. It also does not report a multiplicity adjustment, a testing hierarchy for secondary outcomes, or how the family of outcomes was to be interpreted. Those procedures are not reported in the registry record; their absence from the record does not establish that no such procedures existed in the full study documents.
Multiplicity matters when several outcomes and comparisons are evaluated. In general, testing many hypotheses without an adjustment can make isolated small p-values less persuasive as confirmatory findings. The disease-control and pharmacokinetic comparisons are unadjusted recalculations, and the registry lists additional secondary outcomes without posting results for all of them. Their p-values, where posted, should not be read as if they were results from a single prespecified primary test.
The primary population is described as the Full Analysis Set, comprising all randomized patients. That provides a clear population definition for the primary endpoint in the registry record. The record does not give details about the analysis populations used for each secondary endpoint, the treatment of participants with missing measurements, or the assumptions and methods used for missing data. It also does not describe whether the primary analysis followed the assigned treatment regardless of treatment discontinuation.
The posted denominators vary across outcomes and differ from the primary arm sizes. For example, the adverse-event at-risk counts and the pharmacokinetic group sizes are not the same as the randomized arm sizes. The registry record does not explain these differences, so they should not be attributed to a particular reason. In general, outcome-specific denominators can reflect the availability of data for that measure, but the handling of missing observations and the reasons for each denominator are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Everolimus + Best Supportive Care (BSC) | 171 | 361 | 47.4% |
| Placebo + Best Supportive Care | 64 | 182 | 35.2% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Everolimus + Best Supportive Care (BSC) | 343 of 361 |
| Placebo + Best Supportive Care | 147 of 182 |
Most frequent serious adverse event terms
| Event term | Organ system | Everolimus + Best Supportive Care (BSC) | Placebo + Best Supportive Care |
|---|---|---|---|
| Ascites | Gastrointestinal disorders | 13 of 361 | 11 of 182 |
| Pneumonia | Infections and infestations | 18 of 361 | 1 of 182 |
| Anaemia | Blood and lymphatic system disorders | 14 of 361 | 3 of 182 |
| Abdominal pain | Gastrointestinal disorders | 9 of 361 | 8 of 182 |
| Pyrexia | General disorders | 14 of 361 | 2 of 182 |
| Renal failure | Renal and urinary disorders | 11 of 361 | 2 of 182 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 9 of 361 | 4 of 182 |
| Asthenia | General disorders | 9 of 361 | 3 of 182 |
| Hepatic cirrhosis | Hepatobiliary disorders | 8 of 361 | 3 of 182 |
| Hyperbilirubinaemia | Hepatobiliary disorders | 5 of 361 | 5 of 182 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Everolimus + Best Supportive Care (BSC) | Placebo + Best Supportive Care |
|---|---|---|---|
| Stomatitis | Gastrointestinal disorders | 142 of 361 | 9 of 182 |
| Decreased appetite | Metabolism and nutrition disorders | 114 of 361 | 27 of 182 |
| Oedema peripheral | General disorders | 100 of 361 | 25 of 182 |
| Fatigue | General disorders | 90 of 361 | 30 of 182 |
| Diarrhoea | Gastrointestinal disorders | 94 of 361 | 25 of 182 |
| Cough | Respiratory, thoracic and mediastinal disorders | 79 of 361 | 23 of 182 |
| Pyrexia | General disorders | 86 of 361 | 13 of 182 |
| Pruritus | Skin and subcutaneous tissue disorders | 64 of 361 | 29 of 182 |
| Rash | Skin and subcutaneous tissue disorders | 76 of 361 | 16 of 182 |
| Asthenia | General disorders | 59 of 361 | 31 of 182 |
Serious events with the highest arm-level rate: ascites (6.0%), pneumonia (5.0%), abdominal pain (4.4%), anaemia (3.9%), pyrexia (3.9%).
The registry lists serious adverse events for the everolimus-plus-BSC group among 361 participants at risk and for the placebo-plus-BSC group among 182 participants at risk. It reports 171 affected participants in the everolimus group and 64 in the placebo group. For other adverse events, the corresponding at-risk counts are 361 and 182, with 343 and 147 affected participants. These are counts of participants reported as affected, not estimates of the causal effect of treatment.
The listed serious adverse event terms are ascites at 6.0%, pneumonia at 5.0%, abdominal pain at 4.4%, anaemia at 3.9%, pyrexia at 3.9%, and renal failure at 3.0%. The registry record does not clarify in this summary whether these term percentages are presented by treatment group, so they should not be used to make a direct arm-to-arm comparison.
Adverse event counts require context about definitions, exposure time, severity, and how events were attributed and collected. Those details are not reported in the registry record. Death counts within the adverse-event data are not reported in the registry record. The serious and other adverse-event figures should be read as descriptive safety reporting, not as proof that an event was caused by a study treatment.
12. What the Result Does, and Does Not, Mean
The posted overall-survival results show arm-specific median estimates: 7.56 months for everolimus plus BSC and 7.33 months for placebo plus BSC. The registry also gives 95% confidence intervals for those medians. These figures describe the observed survival summaries in the randomized groups, but they do not by themselves quantify the relative treatment effect over the full follow-up period.
The record says the primary comparison was to use a stratified log-rank test, yet the sponsor-reported comparative result is not reported in the registry record. In particular, the record does not provide the primary hazard ratio, its confidence interval, or the test p-value. Therefore the posted medians alone cannot establish the statistical evidence for a difference between the treatment groups or the precision of a comparative effect estimate.
The secondary results address disease control and drug concentrations, among other listed outcomes. Those results may add context about what was measured, but they cannot stand in for the primary survival result. The unadjusted secondary comparisons also should not be interpreted as confirmatory without information about multiplicity and the planned analysis strategy.
In general, a randomized and double-blind design is intended to support a fair comparison and reduce some forms of bias. It does not guarantee that every registry result is complete or that every estimate is precise. The record gives the primary analysis population and planned test, but does not report important details such as missing-data procedures, stratification factors, or the primary comparative estimate.
Accordingly, the registry record supports a descriptive account of the posted arm medians, their intervals, and selected secondary and safety data. It does not support a definitive statement about the size or statistical significance of the primary treatment contrast. A median difference should not be inferred by subtracting the arm estimates, and absence of a posted comparative result should not be treated as evidence of no effect.
13. Why This Trial Matters Statistically
This trial illustrates why arm-level summaries and a treatment comparison answer different statistical questions. The median survival estimates describe each randomized group separately. The primary question, however, concerns the relative survival experience between groups, for which the registry specifies a stratified log-rank test. Without the sponsor-reported comparison estimate and test result, the primary endpoint remains incompletely characterized in the registry record.
It also illustrates the value of distinguishing the primary endpoint from secondary outcomes. Disease control, performance and quality-of-life measures, and pharmacokinetic assessments may each be informative, but they measure different things. An unadjusted secondary comparison cannot replace the primary time-to-event analysis, especially when the record does not describe multiplicity handling or report all listed secondary results.
Another statistical distinction concerns analysis populations and denominators. The primary population is defined as all randomized patients, while posted outcome-specific group sizes vary. These differences matter for interpretation, but the registry record does not explain the denominators or the associated missing-data methods. Readers should not assume that all outcomes use the same participants or analysis rules.
Finally, the sample-size illustrations based on observed effects are planning exercises rather than measures of the completed trial's observed power. They depend on assumptions stated for the illustrations and do not document the protocol's design rationale. Taken together, the record is useful for identifying the randomized design, the endpoint definition and selected descriptive results, while also showing why a complete statistical interpretation depends on reporting the primary comparative analysis and its uncertainty.
14. 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.
A central limitation of the available registry record is that it posts the primary arm medians and their confidence intervals without the sponsor's comparative overall-survival result. The hazard ratio, comparative confidence interval and log-rank test result are not reported in the registry record. This prevents direct assessment of the estimated treatment contrast and its precision from the posted primary results.
The record does not report the stratification factors for the stated stratified log-rank test, nor does it provide details of the randomization procedure or masking implementation. It also does not describe censoring rules, missing-data handling, or whether the primary analysis included all randomized patients according to assignment. The Full Analysis Set is defined as all randomized patients, but further analysis details are not reported in the registry record.
Some listed secondary outcomes do not have posted results, and the secondary comparisons that are present are not accompanied by sponsor-reported analyses. The record does not state how multiplicity was handled or identify a formal hierarchy across secondary outcomes. The pharmacokinetic groups are identified as 7.5mg and 5mg groups, but the reason for the group sizes and their relation to treatment exposure is not reported in the registry record.
Safety summaries include affected counts and selected serious adverse event terms, but the record does not provide the context needed to evaluate exposure-adjusted rates or causality. The death count in the adverse-event data is not reported. These reporting gaps limit interpretation of the posted data; they should not be mistaken for evidence that the corresponding analyses or procedures were absent from the full study documentation.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma. — NCT01035229.
- Registry record last updated 2016-09-22; status last verified 2016-08.
- Results first posted 2014-10-27.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
The registry record describes EVOLVE-1 as a completed, randomized, phase III, double-blind, placebo-controlled, multicenter study of everolimus plus best supportive care versus placebo plus best supportive care in adults with advanced hepatocellular carcinoma after sorafenib failure or intolerance. Enrollment is listed as 546, with start recorded as 2010-04 and primary completion as 2013-10.
Overall survival was the primary endpoint, defined from randomization to death from any cause, with a stated analysis time point when 454 OS events were observed. The posted medians are 7.56 months and 7.33 months, respectively, with arm-specific 95% confidence intervals. The sponsor-reported primary comparison is not reported in the registry record. Selected disease-control, pharmacokinetic and safety results are also posted, but the record does not include results for every listed secondary outcome or detailed analysis and missing-data procedures.