Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma (NCT01727336), a randomized phase 2 study. The primary outcome is Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability..

2. Clinical Question

This distinction matters when interpreting the results. The title and study summary describe a randomized, double-blind phase 2 investigation with a Part 2 comparison, but the registered primary outcome is a Part 1 safety count. The posted efficacy outcomes include objective response rate and disease control rate for Part 2. The registry record does not report a Part 2 progression-free-survival result among the posted secondary outcomes listed for analysis.

3. Trial Design

The study is registered as a phase 2 randomized trial with quadruple masking and a sequential model. Its planned enrollment was 160 participants. The registry status is terminated, and the record lists a start in 2012-12 and primary completion in 2017-06. The reason for termination is not reported in the registry record; the status alone does not establish why the study ended.

The trial had two parts with different aims. Part 1 assessed safety and tolerability across dalantercept dose levels and sought a recommended dose for Part 2. The listed Part 1 dose levels were 0.6 mg/kg, 0.9 mg/kg, 1.2 mg/kg, and 1.5 mg/kg. The posted Part 1 safety counts include participants at the first three dose levels, while the 1.5 mg/kg arm has no participants in the posted outcome data. The registry reports 0.9 mg/kg as the recommended dose for Part 2.

Part 2 compared dalantercept 0.9 mg/kg plus axitinib with placebo plus axitinib. This preserves axitinib in both groups, so the intended contrast concerns the addition of dalantercept rather than axitinib versus no axitinib. Random assignment and masking are features of the registered design; details about how assignment was generated, how masking was maintained, and whether it was successful are not reported in the registry record.

The study summary describes Part 2 as assessing progression-free survival. The registered primary outcome instead concerns Part 1 adverse events, while posted Part 2 results include objective response rate and disease control rate. This difference between the overall study aim and the primary outcome is important: results for the posted Part 2 response measures should not be treated as if they were the primary endpoint. The registry record does not report the full protocol or a detailed statistical analysis plan.

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.

Before assignment: In the Part 1 dose escalation portion of the study, 4 dose levels of dalantercept plus an expansion cohort were planned. However, dose escalation was suspended following the 1.2 mg/kg dose level and additional subjects were added to the 1.2 mg/kg dose cohort, which represented the expansion; no subjects were enrolled in the 1.5 mg/kg dose level.

Part 1 Dalantercept Dose Escalation

Reasons for not completing this period:

Part 2 Blinded

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set (SAF) consisted of all patients who received at least 1 dose of study drug

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: No subjects were enrolled into the 1.5 mg/kg dose escalation cohort

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability., measured over Assessed from time of first dose to approximately 30 days after last dose. Participants were allowed to remain on treatment until documented disease progression. The time frame for Part 1 of the study was up to 21.6 months.

The primary outcome is the number of Part 1 participants with adverse events. It is a count of participants meeting the event definition, not a continuous measure of symptom severity and not a time-to-event measure. The registry describes assessment from the first dose to approximately 30 days after the last dose. Participants could remain on treatment until documented disease progression, and the Part 1 time frame was up to 21.6 months.

The Safety Analysis Set consists of patients who received at least 1 dose of study drug. The endpoint was intended to support evaluation of safety and tolerability and to help determine the recommended dalantercept dose for Part 2. A participant count gives a direct description of how many people experienced an adverse event within the defined safety population. It does not by itself describe the event’s severity, duration, timing, relationship to study treatment, or whether one participant experienced multiple events.

In the posted Part 1 counts, the recorded numbers of participants with adverse events equal the corresponding participant counts for the 0.6 mg/kg, 0.9 mg/kg, and 1.2 mg/kg arms. No participants are recorded in the 1.5 mg/kg arm. The registry also reports 0.9 mg/kg as the recommended dose for Part 2. These counts describe the registered safety outcome; they do not establish the comparative efficacy of the Part 2 regimens or answer the Part 2 progression-free-survival question.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help distinguish what the posted counts can establish from what remains uncertain. The Part 1 endpoint is a binary event indicator at the participant level: each person either meets the adverse-event outcome definition or does not. The reported value is the number of participants with an event. For this kind of outcome, comparisons may be expressed as differences in event proportions or as relative measures. The registry’s Part 1 primary result is reported as counts and a recommended dose, rather than as a comparative estimate with uncertainty.

What does a risk difference describe?

A risk difference is the event proportion in one group minus the event proportion in the comparison group. A value of zero corresponds to no difference in the proportions. Positive and negative values indicate direction according to the order of groups used in the comparison. The Part 2 posted comparisons use the risk difference for objective response rate and disease control rate. Their confidence intervals include zero, so the data are compatible with no difference as well as with differences in either direction over the interval. A confidence interval is an estimate of uncertainty under the analysis method; it is not a guarantee that the true effect lies within its limits.

Counts and proportions answer related but distinct questions. Counts describe how many participants met an outcome, while a proportion places that count in relation to the number analyzed. The group sizes are not identical, so comparing raw counts alone would not be an adequate comparison. The unadjusted comparisons use the group sizes as well as the event counts. The registry record does not report a sponsor analysis for either posted Part 2 response endpoint.

How should p-values be read?

A p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the model assumptions held. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. The unadjusted p-values are 0.458 for objective response rate and 0.91 for disease control rate. Neither provides evidence against a no-difference null at conventional levels, but neither proves no effect. The estimates and their confidence intervals are essential because they convey possible effect sizes and uncertainty, not just whether a test crosses a threshold.

“Unadjusted” means the reported p-values have not been adjusted for the possibility of multiple statistical tests. The record includes multiple secondary outcomes, but the statistical plan for handling multiplicity is not reported in the registry record. When many outcomes are examined, the chance of at least one apparently notable result can increase. That is why secondary findings are ordinarily interpreted more cautiously than a prespecified primary analysis, particularly when the testing hierarchy and adjustment strategy are not available.

What do the planning illustrations represent?

The sample-size illustrations use the observed effect as a starting point and apply the stated fractions of that effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For the objective response comparison, the illustration gives participants per arm for 80% power and 90% power at 100%, 75%, and 50% of the observed effect. The corresponding values are 845 and 1,130; 1,537 and 2,056; and 3,534 and 4,730. For disease control, the corresponding values are 36,407 and 48,738; 65,009 and 87,028; and 146,911 and 196,671.

These calculations are planning illustrations, not the trial’s original design calculations. They use effects estimated from the posted results, which are uncertain, and they do not mean the completed trial had the stated power. Smaller assumed effects lead to larger planning requirements because a subtler group difference is harder to distinguish from random variation. A future design would also depend on its endpoint definition, analysis method, target population, and other planning choices. The registry record does not report the study’s own sample-size justification.

Why do the analyses differ by endpoint?

Different outcomes require different statistical approaches. A participant-level count of people with an event is binary, whereas progression-free survival is a time-to-event outcome that incorporates event timing and censoring. The registry record’s Part 1 safety endpoint is a binary count; the posted Part 2 response measures are also presented as participant counts. The study summary’s reference to progression-free survival does not make the response analyses substitutes for a time-to-event analysis. The registry record does not report a Part 2 progression-free-survival estimate in the outcome results.

Masking and randomization are design protections against some forms of bias, but they do not eliminate uncertainty or guarantee comparable follow-up, complete data, or adherence to the planned analysis. The registry lists randomized allocation and quadruple masking, but it does not give enough detail to assess implementation. Similarly, the Safety Analysis Set definition is stated for the primary outcome, while the exact analysis population rules for each secondary endpoint are not reported in the registry record. Interpretation should therefore remain anchored to the outcome-specific denominators and definitions that are posted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Part 1 Dalantercept 0.6 mg/kg", "Part 1 Dalantercept 0.9 mg/kg", "Part 1 Dalantercept 1.2 mg/kg")
n      <- c(6, 9, 14)
events <- c(6, 9, 14)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Part 1 Dalantercept 0.6 mg/kg  6  6  100.0  54.1  100.0  61.0  100.0  59.0  99.6
ARM  Part 1 Dalantercept 0.9 mg/kg  9  9  100.0  66.4  100.0  70.1  100.0  69.2  99.7
ARM  Part 1 Dalantercept 1.2 mg/kg  14  14  100.0  76.8  100.0  78.5  100.0  78.2  99.8

11. Analyses Reported by the Sponsor

The registry record’s reported Part 1 analysis names 0.9 mg/kg as the recommended dalantercept dose for Part 2. That is a dose-selection result, not a comparative efficacy estimate. The record does not post a sponsor-reported statistical comparison for the Part 2 objective response or disease control outcomes. Their risk differences, confidence intervals, and unadjusted p-values are therefore best understood as the posted unadjusted comparisons, rather than as a replication of a sponsor efficacy analysis.

No discrepancy is identified between a sponsor analysis and a recalculation in the registry entries. The sponsor’s own analysis would take precedence if a discrepancy were identified, but that situation does not arise in these results. The available primary outcome result is the recommended-dose value, while the secondary response outcomes have no reported sponsor analyses listed. It is not possible to infer from that absence whether a separate analysis was performed outside the registry record.

The primary outcome also differs from the Part 2 efficacy question described in the study summary. The reported dose recommendation belongs to Part 1, whereas the response and disease-control comparisons belong to Part 2. Keeping those roles distinct avoids treating a dose-selection statement as evidence about comparative efficacy.

12. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity strategy for the many secondary outcomes listed across Part 1 and Part 2. It does not state whether the outcomes were ordered in a hierarchy, whether a family-wise error procedure was applied, or whether any p-value adjustment was planned. The Part 2 response p-values are explicitly unadjusted. When several outcomes are analyzed, the chance of at least one apparently unusual result can be greater than for a single test. Without a stated strategy, secondary comparisons are best treated as exploratory and interpreted alongside their effect estimates and uncertainty.

The primary outcome is a Part 1 safety count and the record reports the recommended dose for Part 2. It does not report a hypothesis-testing framework for this dose-selection result. The study summary describes Part 2 progression-free survival as an aim, but the registry record does not provide its statistical analysis details or a result in the posted analyses. Details such as interim analyses, stopping boundaries, prespecified subgroup analyses, and the handling of repeated assessments are not reported in the registry record.

Some population information is available: the primary safety analysis set consists of patients who received at least 1 dose of study drug. The Part 2 response results have their own posted group denominators. However, the registry record does not give a complete participant-flow account for every outcome, explain how missing outcome values were handled, or establish whether all randomized participants were included in each efficacy analysis. It also does not report imputation methods or sensitivity analyses for missing data.

These omissions limit assessment of whether the reported analysis populations followed an intention-to-treat approach, whether exclusions could affect comparability, and how robust the results are to missingness assumptions. The stated denominators remain useful for interpreting the posted counts, but they do not fill in those methodological details. The registered masking and randomization features do not resolve uncertainty about analysis populations, missing-data handling, or multiplicity.

13. 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: pulmonary embolism (16.7%), dyspnea (16.7%), renal failure acute (14.3%), convulsion (11.1%), oedema peripheral (7.1%).

The Part 1 serious adverse event figures are counts of affected participants within each listed group. The registry records 2 of 6 participants in the 0.6 mg/kg group, 1 of 9 in the 0.9 mg/kg group, and 6 of 14 in the 1.2 mg/kg group as having serious adverse events. The 1.5 mg/kg group has no participants recorded. These small dose-group counts are descriptive; they do not establish a comparative safety ranking.

For Part 2, serious adverse events are recorded for 19 of 62 participants receiving dalantercept plus axitinib and 16 of 64 receiving placebo plus axitinib. Deaths are recorded for 20 and 16 participants, respectively. These figures do not, by themselves, show that a death or serious adverse event was caused by study treatment. The registry record does not provide the causal attribution or detailed timing needed to make that determination from these counts.

The listed serious-event terms include pulmonary embolism and dyspnea, each reported as 16.7%; renal failure acute at 14.3%; convulsion at 11.1%; and oedema peripheral and bile duct stenosis, each at 7.1%. The record’s summary of serious terms is not a complete account of event severity, duration, recurrence, or treatment relationship. These safety counts should be read as descriptive summaries within the reported groups, not as proof of causation or as a complete safety profile.

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

The results support a limited set of conclusions about what was recorded. In Part 1, the registry reports adverse-event participant counts for the dose groups with participants and names 0.9 mg/kg as the recommended dose for Part 2. In Part 2, the posted objective response and disease control comparisons do not show a clear statistical separation between dalantercept plus axitinib and placebo plus axitinib. Their uncertainty intervals include no difference, and the unadjusted p-values do not provide strong evidence against that possibility.

Those observations do not establish that the groups are equivalent, that either regimen has no effect, or that an effect of a particular size is ruled out. Equivalence or noninferiority requires a prespecified framework and appropriate margins; such a framework is not reported in the registry record. Nor do the response outcomes settle the progression-free-survival question described in the study summary. They measure different endpoints and cannot substitute for an unreported time-to-event result.

The trial’s termination status is recorded, but the reason is not reported in the registry record. It should not be attributed to safety, efficacy, recruitment, or another cause without documentation. Likewise, the safety counts do not establish that events or deaths were caused by treatment. They describe event counts within defined groups, with limited information about attribution and context.

The planning illustrations are not evidence about what the trial was powered to detect. They use the observed secondary effects and stated assumptions to illustrate potential sample sizes for future studies. Their large values should not be treated as a finding about clinical importance or as a definitive design recommendation. The original sample-size rationale, detailed statistical plan, missing-data methods, and full analysis populations are not reported in the registry record.

15. Why This Trial Matters Statistically

This trial illustrates why the registered primary endpoint and the broader study question need to be kept separate. The study summary presents Part 2 as a test of whether adding dalantercept prolongs progression-free survival. The primary outcome posted in the record is instead a Part 1 safety count intended to guide dose selection. The Part 2 response results are secondary outcomes, and they cannot answer the survival question by proxy.

It also illustrates how randomized design features and statistical evidence serve different purposes. Randomization and masking are intended to support fair comparisons, while confidence intervals and p-values describe uncertainty in the outcomes. Neither the design label nor a single p-value removes uncertainty. In this record, the response comparisons have confidence intervals that include no difference, but that does not prove identical effects. Reporting counts together with group denominators and uncertainty is essential to avoid overreading raw event totals.

The distinction between a dose-selection result and an efficacy comparison is especially important in a sequential study. Part 1 identified 0.9 mg/kg as the recommended dose for Part 2; Part 2 then compared that dose plus axitinib with placebo plus axitinib. A conclusion from the first part should not be carried over as a conclusion about the second part’s efficacy.

Finally, registry records can leave important analytic questions unanswered. Here, multiplicity procedures, missing-data methods, the study’s own sample-size justification, and several details of the statistical plan are not reported in the registry record. The planning illustrations can clarify assumptions for future research, but they are not a replacement for those original design details. Recognizing these boundaries is central to interpreting clinical trial statistics responsibly.

16. 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.

Several limitations are specific to the available record. The study is marked terminated, but the reason for termination is not reported in the registry record. The planned enrollment was 160, while the posted Part 2 response comparisons include 58 and 61 participants. The record does not provide a full participant-flow account explaining enrollment, allocation, exclusions, or the analysis set for each outcome.

The primary outcome is restricted to Part 1 safety and dose selection. It does not directly test the Part 2 efficacy question. Although the study summary identifies progression-free survival as a Part 2 purpose, a Part 2 progression-free-survival result is not included among the results interpreted. The posted Part 2 response measures therefore offer only a partial view of the intended efficacy assessment.

The record does not report a complete statistical analysis plan, a multiplicity adjustment strategy, or methods for missing data. It also does not provide detailed definitions for all secondary outcomes, the outcome-specific analysis populations, or sensitivity analyses. These omissions make it difficult to assess how closely the posted analyses follow prespecified methods and how robust they are to alternative assumptions.

For the Part 1 safety outcome, the 1.5 mg/kg arm has no participants recorded, and the other dose groups are limited in size. The resulting counts are descriptive and cannot support a stable comparative safety estimate across all listed doses. Serious adverse event and death counts also do not state causal attribution in the figures. The record’s term-level serious-event percentages do not provide all the context needed to assess timing, recurrence, or severity.

Finally, the planning illustrations are based on observed effects rather than the trial’s original design justification. Because observed effects are uncertain, the resulting future sample-size figures should be considered assumption-dependent illustrations, not definitive requirements.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma — NCT01727336.
• Registry record last updated 2022-10-06; status last verified 2021-09.
• Results first posted 2021-05-24.
• 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.

20. Record Summary

NCT01727336 is a phase 2 randomized, quadruple-masked, sequential study in advanced renal cell carcinoma. It planned enrollment of 160 participants and is listed as terminated. Part 1 assessed dalantercept safety and tolerability across dose levels, with 0.9 mg/kg reported as the recommended dose for Part 2. The registered primary outcome was the number of Part 1 participants with adverse events.

Part 2 compared dalantercept 0.9 mg/kg plus axitinib with placebo plus axitinib. The study summary describes progression-free survival as the Part 2 question, while the posted secondary comparisons concern objective response rate and disease control rate. Neither comparison provides clear statistical separation in the posted unadjusted analyses. The registry record does not report the reason for termination, a complete analysis plan, multiplicity handling, or missing-data methods.