Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer (NCT00537095), a randomized phase 2 study. The primary outcome is Time to Tumor Progression.

2. Clinical Question

3. Trial Design

This was a phase II, randomized, double-blind, placebo-controlled, parallel-group, multicentre study sponsored by Genzyme, a Sanofi Company. Its official title describes locally advanced or metastatic papillary or follicular thyroid carcinoma in participants failing or unsuitable for radioiodine therapy. The registry lists enrollment of 164 and records the trial as completed. The start date was 2007-09-28, and primary completion was 2009-12-02.

Participants were allocated to vandetanib (ZD6474) or placebo. The active regimen was 300 mg by mouth once daily. The registry describes visits weekly for the first 2 weeks, followed by visits at Week 4, Week 8, and Week 12 after randomization, then every 12 weeks thereafter. Radiologic evaluation using RECIST criteria was planned; the primary outcome description specifies modified RECIST V1.0.

After disease progression, participants in both randomized groups were unblinded. They could discontinue blinded treatment and enter follow-up and survival collection, or begin open-label vandetanib at 300 mg. Survival follow-up continued until greater than or equal to 50% of participants had died. The registry also says that participants taking vandetanib at study closure who wished to remain on treatment could continue while the investigator considered that they were obtaining clinical benefit, or until another anti-cancer therapy was given.

The brief summary describes the study as intended to assess whether vandetanib improved progression-free survival and to identify an effect sufficiently promising to warrant follow-up assessment. A detailed randomization procedure, allocation-concealment method, formal sample-size justification, and prespecified statistical analysis plan are not reported in the registry record. The posted primary-outcome groups are 72 for ZD6474 and 73 for placebo; the registry enrollment figure is 164.

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: The main reason for non-randomization was non-respect of eligibility criteria.

Randomized Treatment Period (433 Days)

Reasons for not completing this period:

Open-label Period (590 Days)

Reasons for not completing this period:

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: Analysis was performed on intent to treat (ITT) population which included all randomized participants who received at least one dose of study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Time to Tumor Progression, measured over Time from date of randomization to date of the first documented tumor progression or date of death from any cause (within the 3 months) of tumor assessment.

The primary outcome is time to tumor progression, reported as a median in days with a 95% confidence interval for each randomized group. Its definition starts at randomization and ends at the first documented tumor progression or death from any cause within the specified interval of tumor assessment. The outcome description states that modified RECIST V1.0 was used.

Time-to-event outcomes are useful when the question concerns how long participants remain free of a defined event, while allowing follow-up times to differ. A median identifies the point in the observed time-to-event distribution at which half of the participants have experienced the event or have not, depending on the event-time estimation method. The confidence interval expresses uncertainty around that group-specific median. It is not, by itself, a direct estimate of the treatment contrast.

The registry reports a median of 334 days for ZD6474, with a 95% confidence interval from 232 to 421 days, and a median of 176 days for placebo, with a 95% confidence interval from 119 to 267 days. The record does not give a sponsor-reported hazard ratio, confidence interval for a between-group effect, or p-value for this primary outcome. The endpoint is described as time to tumor progression, whereas the trial summary frames the main objective in terms of progression-free survival. These terms should be read in light of the specific outcome definition posted in the record.

For interpretation, the group medians describe the observed time distributions, but do not establish the size or precision of a comparative effect. A formal comparative estimate would use the event and censoring information over follow-up, which is not posted in this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median time-to-event estimate describe?

A time-to-event endpoint records the time from a defined starting point until a specified event. In this trial, the starting point is randomization and the event is first documented tumor progression or death from any cause within the stated tumor-assessment interval. The registry reports the median event time for each group. A median is a distribution summary, not a direct comparison between groups. It does not describe every participant’s experience or show the shape of the full event-time distribution.

Time-to-event methods can use information from participants whose event has not been observed by the end of their recorded follow-up. Such observations are generally treated as censored rather than as evidence that the event never occurs. The registry record does not report the censoring rules, the estimator used for the medians, or the handling of missing or incomplete outcome assessments. Without those details, the posted medians can be described, but the analysis cannot be fully reconstructed.

How should the confidence intervals be read?

A confidence interval represents uncertainty in an estimate under the statistical method used. The primary outcome has a 95% confidence interval for each group’s median: 232 to 421 days for ZD6474 and 119 to 267 days for placebo. These intervals apply to the separate medians, not to a treatment difference or hazard ratio. A reader should not infer a formal treatment comparison merely from the positions or overlap of two separate intervals. The registry does not report a confidence interval for the between-group primary effect.

What would a hazard ratio add?

In general, a hazard ratio compares the event rates between groups over follow-up, subject to the assumptions of the fitted model. It is a comparative time-to-event measure and differs from comparing medians. The registry’s description of the endpoint says that the analysis is time-to-event, but the record does not report a sponsor hazard ratio, its confidence interval, its p-value, or the model used. Therefore, a hazard-ratio interpretation cannot be made from this record.

How were the secondary comparisons obtained?

The registry posts counts for the binary secondary outcomes. The displayed risk differences and associated intervals and p-values are simple unadjusted recalculations from those summary statistics. A risk difference is the estimated difference in event probabilities between the treatment and comparator groups on an absolute scale. Its sign indicates the direction of the estimated contrast under the stated group ordering. The confidence interval communicates uncertainty; when it includes zero, the data are compatible with no difference as well as with effects in either direction within the interval.

The unadjusted p-value measures how unusual results at least as extreme as those observed would be under a specified null model. It does not give the probability that the null hypothesis is true, and it does not measure clinical importance. No adjustment for testing multiple secondary outcomes is applied to these recalculations. The registry lists no sponsor-reported analyses for the posted secondary outcomes, and the prespecified analysis methods are not reported in the registry record.

What do the planning illustrations mean?

The sample-size illustrations use the observed effect as a planning reference and state assumptions of a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. They consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For disease control, the illustrations list participants per arm for 80% power and participants per arm for 90% power. For example, planning for 75% of the observed effect gives 332 participants per arm for 80% power and 443 participants per arm for 90% power.

For objective response, planning for 75% of the observed effect gives 2,097 participants per arm for 80% power and 2,806 participants per arm for 90% power. For time to death, planning for 75% of the observed effect gives 9,919 participants per arm for 80% power and 13,278 participants per arm for 90% power. The record says time-to-event planning tables use total events, while the other illustrations use participants per arm; the posted time-to-death calculation is nevertheless presented as a binary comparison. These figures are planning illustrations, not observed power, and do not establish that the trial’s actual design used these assumptions. The trial’s own sample-size justification is not reported in the registry record.

What statistical details remain unavailable?

The record does not report the primary comparative model, a primary hazard ratio, the statistical handling of censoring, missing-data procedures, analysis populations, or whether an interim analysis was conducted. It also does not report a multiplicity strategy. These omissions limit the ability to reproduce the sponsor’s analyses or determine how the posted results relate to a prespecified testing hierarchy. General statistical explanations do not fill those gaps; they clarify what the reported estimates mean without implying that a particular method was used.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity adjustment, testing hierarchy, or other strategy for handling the several outcomes. The primary outcome is time to tumor progression, while the posted secondary outcomes are disease control at 6 months, objective response rate, and time to death. Without a prespecified account of how these outcomes were ordered and analyzed, the unadjusted secondary p-values should not be treated as if they were protected confirmatory tests. Testing multiple outcomes can increase the chance of an apparently notable finding under a setting where none of the underlying effects differs from zero. This is a general statistical concern, not a claim about what the sponsor did.

Missing-data methods and analysis populations are not reported in the registry record. The entry does not state whether the primary analysis was intention-to-treat, per protocol, or based on another population, nor does it describe how participants with incomplete tumor assessments were handled. Censoring rules for the time-to-event outcome are also not reported. Those details matter because they define which observations contribute to an estimate and how follow-up ending before an event is treated.

The brief summary describes survival collection through the point at which greater than or equal to 50% of participants had died, but it does not provide a complete statistical account of the time-to-death analysis. No interim analysis plan, stopping rule, or primary analysis plan is reported in the registry record. The trial’s sample-size justification is likewise not reported; the posted planning illustrations are based on observed effects and specified assumptions, rather than being evidence of the original design calculation.

These gaps constrain interpretation. The posted group summaries remain interpretable as registry results, but they do not establish how missing assessments, deviations, multiplicity, or analysis-population choices were handled in the sponsor’s analysis. The record also gives no reported primary comparative estimate with which to assess the treatment contrast directly.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (6.9%), muscular weakness (6.9%), pneumonia (5.2%), ileus (3.4%), intestinal obstruction (3.4%).

The registry lists safety information separately for randomized treatment and open-label treatment periods. During the randomized period, the vandetanib group is recorded with 73 at risk, 20 affected by serious adverse events, and 72 affected by other adverse events; the placebo group is recorded with 72 at risk, 12 affected by serious adverse events, and 65 affected by other adverse events. These are the registry’s posted figures and are not recalculated into rates.

For the open-label periods, the record lists 29 at risk and 12 affected by serious adverse events in the vandetanib/vandetinib group, and 58 at risk and 17 affected in the placebo/vandetinib group. The record also lists other adverse events for these groups. Because these periods involve open-label treatment and different treatment histories, their counts should not be read as a randomized comparison of vandetanib with placebo.

The most frequently listed serious adverse-event terms include abdominal pain and muscular weakness, each at 6.9%, and pneumonia at 5.2%. Ileus, intestinal obstruction, and general physical health deterioration are each listed at 3.4%. These percentages describe the posted terms; they do not by themselves show causation or provide a complete account of severity, duration, or exposure time. Death counts by safety group are not reported in the registry record.

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

The posted primary results show that the estimated median time to tumor progression was 334 days for ZD6474 and 176 days for placebo, with the stated group-specific 95% confidence intervals. These figures describe the registry’s estimates under the endpoint definition using modified RECIST V1.0. They do not, by themselves, establish a comparative effect or its precision. The record lacks a sponsor-reported primary hazard ratio or other comparative analysis, so the magnitude and uncertainty of the primary contrast cannot be assessed from the posted primary outcome alone.

The secondary outcomes provide additional descriptive information, but their simple unadjusted recalculations have confidence intervals that include zero. They are not a substitute for the primary time-to-event analysis, and the registry does not report how multiplicity was handled or provide sponsor-reported analyses for those secondary endpoints. The figures therefore need to be read as estimates with uncertainty, rather than as definitive evidence for or against a treatment effect.

The safety listing reports serious and other adverse-event counts across randomized and open-label treatment periods. The open-label groups are not randomized comparisons, and adverse-event counts do not establish that treatment caused an event. The listed term percentages also do not show the full clinical context for each event. The safety record is one part of the trial results, not a complete benefit-risk assessment.

These results do not determine what treatment is appropriate for an individual, and they should not be interpreted as medical advice. They also do not establish whether results apply to people outside the stated population, to other thyroid cancer settings, or to different regimens. The registry record supports a bounded statistical reading: it reports group-specific medians and selected secondary counts, while important comparative analysis details are not reported.

13. Why This Trial Matters Statistically

This trial is statistically informative because it combines a randomized, double-blind, placebo-controlled design with a time-to-event primary question in a defined population: locally advanced or metastatic papillary or follicular thyroid carcinoma failing or unsuitable for radioiodine therapy. Randomization and blinding are design features intended to support a fair comparison, but they do not replace the need to report the analysis that estimates that comparison.

The registry provides medians and confidence intervals for the primary outcome, which are useful summaries of the observed time distributions. Yet those group-specific summaries are not equivalent to a comparative hazard ratio or another treatment-effect estimate. The record’s absence of a reported primary comparison illustrates why a result should be judged not only by the values in each arm, but also by whether the between-group estimate and its uncertainty are available.

The trial also illustrates how secondary endpoints can be informative without being decisive. Disease control, objective response, and death represent distinct outcomes. Their unadjusted recalculations offer context, but uncertainty and unreported multiplicity procedures limit how strongly they can support conclusions. The planning illustrations demonstrate another important distinction: sample-size calculations based on an observed effect are hypothetical design aids, not a measure of the completed trial’s observed power and not evidence that an effect is established.

Finally, the registry’s safety counts distinguish randomized and open-label periods. That distinction matters because post-progression treatment and treatment history affect how those groups can be compared. Clear reporting of populations, censoring, missing data, analysis methods, and multiplicity would make the evidence easier to interpret and reproduce. The record shows why statistical transparency is essential to understanding what a clinical trial’s posted results do—and do not—support.

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.

The primary outcome is reported as separate group medians with confidence intervals, but a sponsor-reported between-group estimate is not reported in the registry record. A hazard ratio, its interval, and a p-value are also not reported. This prevents a direct assessment of the primary comparative effect from the posted results. The registry’s skip note specifically states that values are missing or not estimable for a two-arm comparison for this median-time endpoint.

The record does not report the time-to-event analysis method, censoring rules, handling of missing tumor assessments, or analysis population. The outcome definition includes death within the specified tumor-assessment interval, but the record does not clarify how events and assessments outside that interval were handled. These omissions limit reproducibility and make it difficult to assess the sensitivity of the primary result to analysis choices.

The registry enrollment figure is 164, while the posted primary-outcome denominators are 72 for ZD6474 and 73 for placebo. The record does not explain this relationship, so the figures should be reported as listed rather than reconciled by assumption. Safety-period denominators also differ from the primary-outcome group denominators. The open-label safety groups reflect treatment after progression and are not randomized comparisons.

Secondary analyses are simple unadjusted recalculations from posted counts, and sponsor-reported analyses are not listed. The record does not report a multiplicity strategy, formal sample-size justification, or interim analysis plan. The sample-size illustrations use observed effects and stated assumptions, so they cannot establish the trial’s original design adequacy or observed power. These limitations are specific to the information in this registry record and do not determine what may be reported elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy and Safety of Vandetanib (ZD6474) in Patients With Metastatic Papillary or Follicular Thyroid Cancer — NCT00537095.
• Registry record last updated 2024-04-19; status last verified 2023-11.
• Results first posted 2011-07-08.
• 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.

18. Record Summary

NCT00537095 is a completed, randomized, double-blind, placebo-controlled, parallel-group phase II trial sponsored by Genzyme, a Sanofi Company. It studied vandetanib (ZD6474) in locally advanced or metastatic papillary or follicular thyroid carcinoma in participants failing or unsuitable for radioiodine therapy. Registry enrollment is 164; the trial started on 2007-09-28, with primary completion on 2009-12-02.

The primary outcome is time to tumor progression, defined from randomization to first documented progression or death from any cause within the stated tumor-assessment interval, using modified RECIST V1.0. The registry reports a median of 334 days for ZD6474 and 176 days for placebo, with group-specific 95% confidence intervals, but no sponsor-reported primary comparative estimate.

Posted secondary outcomes cover disease control at 6 months, objective response rate, and time to death. Their unadjusted recalculations have confidence intervals that include zero. Safety counts are listed separately for randomized and open-label treatment periods. Analysis methods for the primary comparison, missing-data handling, analysis populations, and multiplicity procedures are not reported in the registry record.