Efficacy and Tolerability of ZD6474 in Patients With Thyroid Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Tolerability of ZD6474 in Patients With Thyroid Cancer (NCT00098345), a na phase 2 study. The primary outcome is Objective Response Rate.

2. Clinical Question

In practical terms, the study asked whether objective tumor responses were observed among people receiving vandetanib in this open-label, single-group phase II study. The endpoint definition identifies which response categories count, but a count alone does not describe the proportion of participants who responded unless the relevant analysis denominator is also known. Neither the responder count nor the denominator for the primary analysis is reported in the registry record.

The study also listed secondary outcomes, including progression-free survival, duration of objective response, disease control rate, biochemical response measured with calcitonin, symptomatic response, and World Health Organisation performance status. Their inclusion indicates that the study was intended to describe outcomes beyond objective response. Results for those outcomes are not reported in the registry record, so their definitions and findings cannot be assessed from this record alone.

3. Trial Design

This was a phase II, open-label, two-stage study of ZD6474, also called vandetanib, in patients with locally advanced or metastatic hereditary medullary thyroid carcinoma. The registry record describes a single-group model, no allocation, and no masking. Those design features mean that the study was not set up as a randomized, masked comparison against a concurrent control group. The intervention description identifies Caprelsa (vandetanib) 300 mg as a daily oral dose.

The recorded enrollment was 40. The study status is completed; the recorded start was 2004-11 and primary completion was 2008-02. These registry dates and enrollment describe the trial record, but they do not establish how many participants received treatment, had evaluable primary-outcome data, or were included in an analysis. Those details are not reported in the registry record.

The primary endpoint was Objective Response Rate, expressed as the number of participants with a confirmed best objective response of complete response or partial response under RECIST 1.0. Assessment was scheduled pre-dose and every 12 weeks up to RECIST progression. The record does not give an observed response count, a response proportion, a confidence interval, or a statistical test for that endpoint.

The record lists seven outcome measures and names several secondary outcomes, including progression-free survival and duration of objective response. It also lists disease control rate, calcitonin biochemical response, symptomatic response, and WHO performance status. It does not report outcome results or analysis details for these measures. The record lists zero analyses, which means no analysis entries are included in the registry record; it does not establish what analyses may have been conducted outside that record.

A two-stage label alone does not disclose how the stages were organized, what decision rules were used, or whether any interim assessment occurred. Those design details are not reported in the registry record. Likewise, the record does not report a comparator-based treatment effect, a prespecified statistical analysis plan, or a sample-size justification for the study itself. The sample-size assumptions described for a planning illustration should not be confused with the trial’s own design.

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: 40 patients were enrolled/screened to the study but only 30 patients were entered treatment/randomized.

Overall Study

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.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate, measured over Pre-dose and every 12 weeks up to RECIST progression as defined according to RECIST 1.0..

The primary endpoint, Objective Response Rate, was defined as the number of patients whose best objective response was a confirmed complete response or partial response according to RECIST 1.0. These categories classify tumor response under the stated criteria. The endpoint’s timeframe was pre-dose and every 12 weeks up to RECIST progression. The registry record therefore specifies the response categories and the planned assessment schedule.

Objective response is used in clinical studies to describe whether participants meet defined criteria for tumor shrinkage, rather than relying only on symptoms or a laboratory measure. As a general statistical concept, a response count is a binary-outcome summary: each participant is classified according to whether the qualifying event occurred. A response proportion can be estimated only when the relevant denominator is specified alongside the count. The record describes the primary measure as a number of participants and does not report the observed count or the analysis denominator, so an observed rate cannot be assessed from the record.

The endpoint definition also requires confirmation and uses the best objective response, not simply an unconfirmed observation at one assessment. That distinction matters because a response endpoint depends on both the criteria for response and the rules for confirmation and assessment. Although the registry record names RECIST 1.0 and the assessment timing, it does not report further operational details, such as how confirmation was handled in the analysis or how participants without a post-baseline assessment were treated. Those details are not reported in the registry record.

The endpoint can describe observed responses in the treated group, but by itself it cannot establish how outcomes would have differed under another treatment or no treatment. That limitation follows from the single-group design and the absence of a concurrent comparator.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record gives a concise description of the trial design and primary endpoint, but it does not report a statistical analysis plan or any analysis entries. The concepts below explain how the listed design and endpoint are generally interpreted; they do not imply that a particular analysis was performed in this study.

What does a single-group design estimate?

A single-group study observes outcomes among participants receiving the study intervention. For a binary endpoint such as whether a participant meets the response definition, an analysis may report the number meeting the definition and, when an analysis denominator is available, the corresponding proportion. The registry record defines responders as participants with a confirmed best objective response of complete response or partial response according to RECIST 1.0. It reports neither the responder count nor the denominator for the primary analysis.

Without a concurrent comparator, the study does not directly estimate a difference between treatment groups. A response observed in a single group may be described, but interpretation as a treatment effect requires caution because outcomes may also reflect the enrolled population, disease course, assessment practices, and other factors. This is a general limitation of single-group designs, not a claim about what caused any particular outcome in this study.

Why does the assessment schedule matter?

The primary endpoint was scheduled for assessment pre-dose and every 12 weeks up to RECIST progression. Repeated assessment provides opportunities to classify a best response over follow-up, while the stated stopping point links assessment to progression. In general, timing and confirmation rules can affect which observations qualify as a best response. The registry record does not report further details about confirmation procedures, missed visits, or the handling of assessments after withdrawal.

What does a confidence interval add?

As a general concept, a confidence interval expresses statistical uncertainty around an estimate under a specified method and assumptions. A narrow interval indicates greater precision than a wide interval, but neither width nor coverage can be evaluated without an estimate and interval. The registry record does not report a primary response estimate or confidence interval. It also does not report the method used to calculate uncertainty for the primary endpoint.

A statistical test, when used, addresses a defined hypothesis under a specified analysis plan. Its interpretation depends on the outcome, population, method, and prespecified threshold. The record does not report a primary hypothesis test, p-value, or the analysis plan that would establish how such a test should be interpreted. No test result can be reconstructed from the endpoint definition alone.

How should the two-stage label be read?

The study is described as two-stage, but the record does not report stage-specific enrollment, interim decision rules, stopping boundaries, or whether results from one stage determined continuation to another. Those details are essential for understanding how a two-stage design controls statistical error and informs enrollment decisions. The label alone does not establish that an interim analysis was performed or indicate what decision rules applied.

What does the sample-size illustration describe?

The stated sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event illustrations, the stated output is a total number of events using the Schoenfeld method; other illustrations are expressed as participants per arm. These assumptions describe planning calculations, not the trial’s single-group design or an observed trial result. The record does not report numerical illustration results or the original trial’s sample-size justification.

As a general principle, a planning calculation depends on the target effect, statistical assumptions, and design. An illustration based on an observed effect is not observed power and does not show that the study had a particular probability of detecting an effect. The actual effect estimate needed to interpret such an illustration is not reported in the registry record.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion occurs when observed variability exceeds what a model assumes. It can make standard errors too small if the model does not account for the extra variation, leading to uncertainty that appears more precise than it is. The primary endpoint is a participant count for a binary response definition, and the registry record does not report a model or an over-dispersion assessment. This general issue should not be read as evidence that over-dispersion was present in this study.

Overall, the record supports a description of the planned endpoint and design, but not an independent evaluation of the statistical analysis. The statistical methods, analysis population, treatment of missing observations, and inferential results are not reported in the registry record.

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("Caprelsa (Vandetanib) 300 mg")
n      <- c(30)
events <- c(6)
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  Caprelsa (Vandetanib) 300 mg  30  6  20.0  7.7  38.6  9.5  37.3  9.6  37.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven outcome measures and identifies the primary endpoint as Objective Response Rate. It also names secondary outcomes, including progression-free survival, duration of objective response, disease control rate, calcitonin biochemical response, symptomatic response, and WHO performance status. Multiple outcomes can raise multiplicity concerns when several hypotheses are tested, because the chance of at least one apparently notable result can increase across a set of tests. This is a general statistical concern; the record does not report which outcomes were formally tested or whether any multiplicity adjustment was planned.

The record lists zero analyses. That means analysis entries are not included in the registry record; it does not establish whether analyses were conducted elsewhere. A prespecified hierarchy, adjustment procedure, or strategy for interpreting secondary outcomes is not reported in the registry record. Without those details and the outcomes themselves, the statistical role of the secondary measures cannot be assessed.

Information about missing data and analysis populations is also not reported in the registry record. The record does not specify the number of participants included in the primary analysis, how participants without evaluable response assessments were handled, whether any participants withdrew before assessment, or whether the analysis used an intention-to-treat or another population. Enrollment of 40 is not a substitute for those details.

These omissions matter because response estimates depend on the analysis denominator and on how unevaluable or missing observations are handled. As a general principle, different missing-data approaches can lead to different estimates and uncertainty. No approach should be assumed for this study. The registry record does not report sensitivity analyses or methods for checking the effect of missing observations.

12. 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: nausea (6.7%), cardiac failure (3.3%), diarrhoea haemorrhagic (3.3%), dysphagia (3.3%), gastric ulcer (3.3%).

The registry record lists safety information for Caprelsa (vandetanib) 300 mg. The serious adverse-event figures are 30 at risk and 14 affected. The other adverse-event figures are 30 at risk and 30 affected. The record also lists 3 deaths. These are the recorded counts; they do not by themselves establish the cause of an event or death, or whether an event was attributable to the intervention.

The listed serious adverse-event terms are Nausea, 6.7%; Cardiac Failure, 3.3%; Diarrhoea Haemorrhagic, 3.3%; Dysphagia, 3.3%; Gastric Ulcer, 3.3%; and Large Intestine Perforation, 3.3%. These entries describe the terms and percentages recorded. The registry record does not provide further event-level details, such as timing, severity grades, outcomes, or attribution.

Safety counts require careful attention to their population and definitions. The recorded number at risk does not match the total enrollment stated for the study, and the registry record does not explain the relationship between the safety population and enrollment. It also does not explain the precise meaning of the other-event category. These figures are descriptive, not a comparison against an untreated or alternative-treatment group. They should not be converted into comparative safety conclusions without additional information.

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

The registry record establishes that this was a completed, open-label, phase II, single-group study of ZD6474, also called vandetanib, in patients with locally advanced or metastatic hereditary medullary thyroid carcinoma. It gives the primary endpoint definition, the assessment schedule, the recorded enrollment, and selected safety information. It does not report the primary response count, an estimated response rate, or statistical analyses.

Accordingly, the record does not show how many participants met the defined response criteria or how precise any response estimate might be. It does not support a conclusion about the magnitude of objective response in the study. Because there is no concurrent comparator, the design also does not provide a randomized estimate of how outcomes differed from another treatment or from no study intervention.

The registry record’s outcome list should be distinguished from outcome findings. Naming progression-free survival, duration of objective response, disease control rate, calcitonin response, symptomatic response, or performance status does not demonstrate what happened for any of those measures. Results for them are not reported in the registry record.

The safety entries likewise have a limited descriptive meaning. They record counts for adverse-event categories, selected serious adverse-event terms and percentages, and deaths. Without further details about the safety population, event timing, attribution, and a comparator, these entries do not establish whether the intervention caused an event or how its safety compares with another option.

In general, a trial record is most informative when it includes outcome estimates, analysis populations, uncertainty measures, and methods that connect the design to the results. Those statistical results and methods are not reported in the registry record. The study can therefore be described by its design and planned measurements, but its efficacy findings cannot be interpreted from the registry information available.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of why design details and result reporting must be read together. The record describes a phase II, open-label, two-stage study, but its model is single group and no allocation is listed. That combination means the record should not be read as a randomized comparison. The two-stage label also does not reveal the decision rules or interim procedures needed to understand the design’s statistical operating characteristics.

The primary endpoint illustrates another important distinction: a definition is not a result. The registry record specifies that the endpoint counts participants with a confirmed complete or partial response under RECIST 1.0 and gives a repeated assessment schedule. It does not report the response count, denominator, estimate, or uncertainty. Without those results, readers cannot assess the observed response frequency or its precision.

The record also shows why enrollment and analysis population should not be treated as interchangeable. Enrollment is recorded as 40, while the primary analysis denominator is not reported. Safety counts refer to populations whose relationship to enrollment is not explained in the record. A sound interpretation therefore depends on knowing who was included in each analysis and how missing assessments were handled.

Finally, the distinction between planning assumptions and trial evidence matters. The sample-size assumptions describe an illustration with equal allocation between two arms, whereas the recorded study model is single group. Such an illustration is not a description of the trial’s design, nor is it observed power. The registry record does not report the trial’s own sample-size justification or numerical planning results.

15. 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 principal limitation for interpreting this study from its registry record is the absence of posted efficacy results. The primary endpoint is defined, but the record does not report the responder count, analysis denominator, response estimate, confidence interval, or statistical test. Secondary outcomes are listed without reported results. The record’s zero analysis entries should be understood as an absence of analyses in the registry record, not proof that no analyses were conducted.

Important design details are also missing. Although the study is described as two-stage, the stage structure, interim procedures, and decision rules are not reported in the registry record. A statistical analysis plan, hypothesis-testing strategy, multiplicity approach, and sample-size justification for the original study are also not reported.

The record does not describe the analysis population or the handling of participants without evaluable outcome data. It does not state whether the primary analysis included all enrolled participants, only treated participants, or another population. The relationship between enrollment and the safety populations is not explained. These omissions prevent a complete assessment of the denominators underlying the reported safety counts and any potential primary result.

For safety, the record lists selected terms and percentages, counts at risk and affected, and deaths, but does not provide further event-level information or comparative safety data. The record does not establish event attribution or cause of death. Because the study is single group, it also cannot provide a randomized comparison of safety or efficacy against another group. These limitations restrict interpretation of what the trial record can establish; they do not indicate what unreported analyses or results might show.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Tolerability of ZD6474 in Patients With Thyroid Cancer — NCT00098345.
• Registry record last updated 2018-05-07; status last verified 2018-04.
• Results first posted 2011-05-24.
• 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.

19. Record Summary

The registry record describes a completed, phase II, open-label, two-stage study of ZD6474 (vandetanib) in patients with locally advanced or metastatic hereditary medullary thyroid carcinoma. It records a single-group model, no allocation, enrollment of 40, a start of 2004-11, and primary completion in 2008-02. The listed intervention is Caprelsa (vandetanib) 300 mg by daily oral dose.

The primary endpoint was the number of participants with a confirmed complete or partial response according to RECIST 1.0, assessed pre-dose and every 12 weeks up to RECIST progression. The registry record does not report the primary response result, secondary outcome results, or statistical analyses. It lists safety counts and selected serious adverse-event terms, but does not explain the safety populations’ relationship to enrollment or provide event-level context. The record therefore describes the study and its intended measurements without providing enough reported results to assess efficacy or comparative effects.