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 A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval (NCT01328054), a na phase 4 study. The primary outcome is Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01328054 |
| Phase | Phase 4 |
| Condition | Cancer |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | Single |
| Enrollment | 58 |
| Arms in the primary outcome | n/a |
| Lead sponsor | GlaxoSmithKline |
| Results posted | Yes |
2. Clinical Question
Population
Participants with advanced solid tumors were the intended study population. The primary analysis population was defined as participants who received at least one dose and met criteria for dosing compliance, ECG acquisition, and baseline ECG acquisition. The number meeting those evaluability criteria is not reported in the registry record.
Intervention
The intervention was repeat oral dosing of lapatinib 2000mg for 2 days, given as three separate doses 12 hours apart. Each dose consisted of 8 tablets. The primary question concerns the effect on cardiac repolarization, measured through QTcF.
Comparator
The comparator was placebo matching lapatinib, administered for 2 days as three separate doses 12 hours apart, with 8 tablets per dose. Participants were not to know when they were receiving placebo or lapatinib. This was a single-sequence crossover study, not a randomized comparison between separate groups.
Primary question
The primary question was whether the baseline-adjusted mean QTcF differed between lapatinib and placebo at pre-dose and specified post-dose time points. QTcF is the QT interval corrected using Fridericia’s method. The planned treatment contrast was estimated at each time point with a 90% confidence interval. Those estimates and intervals are not reported in the registry record, so the size and precision of the primary contrast cannot be described from the posted information.
3. Trial Design
This was a Phase IV, placebo-controlled, single-sequence crossover study in participants with advanced cancer. The registry lists allocation as NA and the model as single group. It also lists single masking; the brief description says participants would not know whether they were receiving placebo or lapatinib. Which other parties, if any, were masked is not reported in the registry record.
The planned treatment period occurred over five days. Participants received placebo for 2 days and lapatinib for 2 days, in the same sequence described in the arm information. Each treatment was given as three doses 12 hours apart. An end-of-study visit was planned for Day 8, or no later than 3 days beyond Day 8. The registry record does not report a washout period or a randomized treatment sequence.
Continuous Holter monitoring was used to obtain ECG recordings, from which digital 12-lead ECG measurements were extracted. Triplicate ECG readings were scheduled at baseline and around dosing on the treatment days. Pharmacokinetic samples were planned immediately after the specified QTc measurements for participants dosed with placebo or lapatinib.
The registry reports enrollment of 58 and status as completed. The start is listed as 2011-12 and primary completion as 2015-03. It does not report how many participants completed each treatment period, how many contributed to the primary analysis, or the reasons for any missing measurements. Participants who completed the study and were eligible could be offered continued lapatinib treatment through a continuation protocol, either alone or with other oncology drugs.
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: All participants (par.) underwent screening assessments within 14 days prior to the start of study treatment to determine their eligibility for enrollment. Study treatment was administered over a period of 5 days, and an End of Study visit was conducted on Day 8-11.
Placebo on Day 1 and Day 2 (2 Days)
| Stage | Placebo | Lapatinib 2000 mg |
|---|---|---|
| STARTED | 57 | 0 |
| COMPLETED | 57 | 0 |
| NOT COMPLETED | 0 | 0 |
Lapatinib on Day 3 and Day 4 (2 Days)
| Stage | Placebo | Lapatinib 2000 mg |
|---|---|---|
| STARTED | 0 | 58 |
| COMPLETED | 0 | 53 |
| NOT COMPLETED | 0 | 5 |
Reasons for not completing this period:
| Reason | Placebo | Lapatinib 2000 mg |
|---|---|---|
| Adverse Event | 0 | 2 |
| Physician Decision | 0 | 1 |
| Withdrawal by Subject | 0 | 2 |
Analysis population for the primary outcome, as defined in the registry: Evaluable Population: all participants in the All-Treated Subjects (ATS) Population who met the criteria for dosing compliance, ECG acquisition, and Baseline ECG acquisition. The ATS Population is comprised of all participants who received at least one dose of study medication (placebo or lapatinib).
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 | Placebo and Lapatinib 2000 mg |
|---|---|---|
| Participants analysed | 58 | |
| Age, Continuous | Years | 55.1 (SD 12.30) |
| Sex: Female, Male: Female | Participants | 37 |
| Sex: Female, Male: Male | Participants | 21 |
| Race/Ethnicity, Customized: African American/African Heritage | Participants | 3 |
| Race/Ethnicity, Customized: Asian - East Asian Heritage | Participants | 1 |
| Race/Ethnicity, Customized: Asian - South East Asian Heritage | Participants | 1 |
| Race/Ethnicity, Customized: White - White/Caucasian/European Heritage | Participants | 51 |
| Race/Ethnicity, Customized: missing | Participants | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Treatment Difference in Duration of Cardiac Ventricular Depolarization and Repolarization Interval (QT) in Fridericia-corrected QT Interval (QTcF) Values Between Placebo and Lapatinib 2000mg, measured over Baseline (BL) (Day1) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours (hr) post-dose on Day 2 for placebo (PBO). Baseline (Day 3) and pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24-hours post-dose on Day 4 for lapatinib (LAP)..
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | Milliseconds |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was the treatment difference in QTcF, measured in milliseconds, between lapatinib 2000mg and placebo. QT is the ECG interval reflecting ventricular depolarization and repolarization. Because heart rate affects the QT interval, the primary endpoint used Fridericia correction to produce QTcF. This correction is intended to make QT measurements more interpretable across heart rates; it does not remove all measurement or model uncertainty.
Holter monitoring captured ECG activity continuously. Three ECG readings were collected at each scheduled time point and averaged before analysis. Baseline was defined separately for each treatment period: the average of the triplicate pre-dose QTcF readings on Day 1 for placebo and on Day 3 for lapatinib. Change from baseline was calculated at each time point, while the primary treatment contrast was described as the baseline-adjusted mean difference in absolute QTcF.
Repeated measurements after dosing allow the study to examine how the treatment contrast varies over time, rather than relying on a single post-dose observation. The registry lists pre-dose and post-dose measurements through 24 hours for each treatment. The endpoint is therefore a continuous measure, summarized as a least-squares mean with a standard error, with a 90% confidence interval planned for the treatment difference at each time point. The actual estimates and intervals are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a plan to estimate treatment differences in QTcF, but it does not give the numerical primary results. In particular, no treatment-difference estimates, standard errors, or 90% confidence intervals are reported for the scheduled time points. It is therefore not possible to state the magnitude, direction, or precision of the primary contrast from the posted information. The absence of a reported estimate should not be read as a finding of no difference.
The intended contrast was between baseline-adjusted QTcF measurements during lapatinib and placebo periods. A confidence interval would indicate the range of treatment differences reasonably compatible with the data and the analysis assumptions. A narrower interval would indicate greater precision, while a wider interval would indicate greater uncertainty. Without the numerical interval, the precision of any contrast cannot be assessed. No significance result for the primary outcome is reported in the registry record.
The design also matters when interpreting the contrast. Participants received both placebo and lapatinib in a single sequence, rather than being allocated to separate randomized groups. The record lists allocation as NA, and the study is described as a single-sequence crossover. Within-person measurements can support a treatment contrast, but the registry’s posted description does not establish that order effects, period effects, or carryover were assessed. Details of any such assessment are not reported in the registry record.
The primary analysis description specifies repeated-measures analysis of variance adjusted for treatment group, time point, and their interaction. This accounts in the model for the scheduled repeated observations and allows the treatment contrast to be estimated at each time point. The registry does not report the model’s covariance specification, diagnostics, or a numerical result. It also does not report a multiplicity adjustment across the multiple time points.
The adverse-event counts are separate from the primary ECG outcome and should not be treated as evidence about the QTcF contrast. The registry lists serious adverse events among 0 of 57 participants in the placebo group and 4 of 58 in the lapatinib group. The study was not a randomized comparison between independent groups, and those figures alone do not estimate a causal difference in risk. They also do not replace the unreported ECG results.
9. Statistical Methods Explained
The primary endpoint is continuous: QTcF is measured in milliseconds, and the registry describes the result as a least-squares mean with a standard error. A continuous outcome preserves the size of the measured difference rather than classifying participants into categories. In this study, the analysis focused on differences between treatment periods at specified times, adjusted for baseline.
How were the ECG measurements defined?
A Holter monitor records cardiac activity over time. The study used continuous Holter recordings to extract digital 12-lead ECGs. Three readings were collected at each scheduled time point, then averaged before analysis. Averaging replicate readings can reduce the influence of short-term measurement variation, although it does not eliminate uncertainty in the treatment estimate.
Baseline was treatment-specific. The placebo baseline was the average of triplicate pre-dose QTcF readings on Day 1; the lapatinib baseline was the corresponding average on Day 3. For each time point, change from baseline was calculated by subtracting the relevant baseline value from the QTcF measurement. The primary description also specifies a baseline-adjusted mean difference in absolute QTcF between lapatinib and placebo. These are related ways of accounting for starting measurements, but the registry does not provide the resulting values.
What does the repeated-measures analysis do?
The stated method was repeated-measures analysis of variance, adjusted for treatment group, time point, and the treatment-group-by-time-point interaction. Repeated-measures methods are used when measurements from the same participant are collected at multiple times. The observations from one participant may be correlated; treating them as unrelated can misrepresent the uncertainty. The analysis described in the registry models the treatment and time structure and estimates a treatment contrast at each scheduled time point.
The treatment-by-time interaction allows the treatment contrast to differ over time. That is relevant because an effect measured shortly after dosing need not have the same size as one measured later. The record does not state the covariance structure used for repeated observations, how model fit was assessed, or how incomplete repeated measurements were handled. Those details are not reported in the registry record.
How should standard errors and confidence intervals be read?
A standard error describes the uncertainty in an estimated mean or contrast under the analysis model. It is not the spread of individual participants’ measurements. The primary outcome description says that a 90% confidence interval was estimated for each treatment difference. In general, a confidence interval expresses uncertainty around an estimate: its width reflects precision, conditional on the model and data. It is not a statement that a particular proportion of participants had values within the interval. Since neither estimates nor intervals are posted, no conclusion about the precision of the QTcF differences can be drawn.
The analysis was described at pre-dose and at 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing for each treatment period. Multiple time-point estimates create multiple opportunities to observe a nominally unusual result. Whether the analysis adjusted for this multiplicity is not reported in the registry record. Without a stated adjustment or a declared primary time point, isolated time-specific results, if available elsewhere, would need to be read in the context of the full analysis plan; the registry does not supply that additional information.
What do the planning assumptions mean?
The sample-size material is described as a planning illustration based on an observed effect, not as the trial’s original design justification. Its assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. For outcomes other than time-to-event outcomes, the illustrations are expressed as participants per arm for 80% or 90% power. Time-to-event illustrations use the total number of events under the Schoenfeld approach.
These are planning calculations, not observed power and not evidence that the trial was designed to achieve a particular level of power. No protocol sample-size justification is reported in the registry record. Because the primary treatment estimate is not reported, the magnitude of the observed effect underlying any such illustration cannot be independently interpreted from the posted results.
10. Multiplicity, Missing Data and Analysis Populations
The primary analysis includes repeated QTcF measurements at several post-dose times for placebo and lapatinib. The registry also lists 16 outcome measures and 10 analyses. Testing or estimating multiple outcomes and time points raises a multiplicity question: when many contrasts are considered, the chance of at least one apparently notable result can increase. Whether the study used an adjustment, a prespecified hierarchy, or another strategy to address multiplicity is not reported in the registry record.
The registry description defines an evaluable population as participants in the all-treated population who met criteria for dosing compliance, ECG acquisition, and baseline ECG acquisition. The all-treated population includes participants who received at least one dose of study medication. This definition identifies who was intended to contribute to the primary analysis, but the number of participants meeting the evaluability criteria is not reported. The record also does not provide the amount or pattern of missing ECG data.
Methods for handling missing primary outcome measurements, deviations from the planned measurement schedule, and incomplete treatment periods are not reported in the registry record. The handling of missing adverse-event or laboratory data is likewise not described in the posted information. The number enrolled is not sufficient to determine the number contributing to each analysis.
The registry does not report whether sensitivity analyses were performed to assess the influence of missing data, nor does it provide a detailed protocol for analysis populations beyond the stated all-treated and evaluable definitions. Those omissions limit assessment of whether the reported analysis, if available, would be robust to incomplete measurements or alternative population definitions.
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 |
|---|---|---|---|
| Placebo | 0 | 57 | 0.0% |
| Lapatinib 2000 mg | 4 | 58 | 6.9% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Placebo | 16 of 57 |
| Lapatinib 2000 mg | 44 of 58 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo | Lapatinib 2000 mg |
|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | 0 of 57 | 1 of 58 |
| Oesophagitis | Gastrointestinal disorders | 0 of 57 | 1 of 58 |
| Hyperbilirubinaemia | Hepatobiliary disorders | 0 of 57 | 1 of 58 |
| Bacteraemia | Infections and infestations | 0 of 57 | 1 of 58 |
| Urinary tract infection | Infections and infestations | 0 of 57 | 1 of 58 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo | Lapatinib 2000 mg |
|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 2 of 57 | 17 of 58 |
| Anaemia | Blood and lymphatic system disorders | 0 of 57 | 9 of 58 |
| Nausea | Gastrointestinal disorders | 4 of 57 | 5 of 58 |
| Fatigue | General disorders | 0 of 57 | 6 of 58 |
| Decreased appetite | Metabolism and nutrition disorders | 0 of 57 | 4 of 58 |
| Abdominal pain upper | Gastrointestinal disorders | 1 of 57 | 2 of 58 |
| Constipation | Gastrointestinal disorders | 1 of 57 | 2 of 58 |
| Dyspepsia | Gastrointestinal disorders | 0 of 57 | 3 of 58 |
| Vomiting | Gastrointestinal disorders | 0 of 57 | 3 of 58 |
| Oedema peripheral | General disorders | 0 of 57 | 3 of 58 |
Serious events with the highest arm-level rate: abdominal pain (1.7%), oesophagitis (1.7%), hyperbilirubinaemia (1.7%), bacteraemia (1.7%), urinary tract infection (1.7%).
The registry lists serious adverse events for 0 of 57 participants at risk in the placebo group and 4 of 58 participants at risk in the lapatinib 2000 mg group. These are participant counts, not a treatment-effect estimate. The record also lists other adverse events for 16 of 57 participants in the placebo group and 44 of 58 in the lapatinib group. These figures should be read as counts within the listed groups, not as a randomized between-group comparison.
The study used a single-sequence crossover design, and allocation is listed as NA. The group denominators differ, and the registry does not provide participant-level pairing, event timing, duration of exposure, or an analysis adjusting for the study design. Therefore, the counts alone do not establish that treatment caused a difference in adverse-event occurrence. They also do not show how many events each participant experienced.
The listed serious terms include abdominal pain, oesophagitis, hyperbilirubinaemia, bacteraemia, and urinary tract infection, each reported as 1.7%. Deaths are not reported in the registry record. The available counts do not provide a complete account of severity, timing, relatedness, or outcomes for every event, and those details are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
This study was designed to estimate how lapatinib 2000mg affected QTcF compared with matching placebo in participants with advanced cancer. The registry describes repeated Holter-based ECG measurement, baseline adjustment, and a repeated-measures analysis. Those details define the intended statistical question, but the posted record does not report the numerical primary treatment differences or their 90% confidence intervals. As a result, the size and precision of the primary result cannot be assessed from the registry record.
The planned measurements at multiple times could describe the time course of the QTcF contrast, if the estimates were available. A point estimate alone would not communicate its precision; a confidence interval would be needed to show the uncertainty associated with that estimate. Neither the numerical estimates nor the intervals are reported. It is consequently not possible to characterize which time points had larger or smaller contrasts, or whether any contrast was statistically distinguishable from zero.
The described analysis does not, by itself, answer every question about cardiac or clinical safety. QTcF is a measured ECG parameter, while adverse events and other ECG findings are separate outcomes. The registry lists adverse-event counts, but those counts do not substitute for the primary QTcF results or establish a causal comparison. Results for the other listed outcomes are not included in the registry information summarized in this record.
The study’s single-sequence crossover structure is also important. The comparison was not a randomized assignment of separate participants to placebo or lapatinib groups. The registry record does not report enough detail to evaluate potential period or carryover effects, the amount of missing outcome data, or the multiplicity strategy. The findings that can be described are therefore limited to the stated design, measurement plan, analysis description, and posted safety counts.
Nothing in the available information establishes an individual participant’s risk or determines how a treatment should be used. The registry record supports a description of the statistical question and planned approach, but not a conclusion about the direction or magnitude of the primary QTcF effect.
13. Why This Trial Matters Statistically
This trial is statistically notable for its repeated-measures crossover structure. Participants were scheduled to receive both placebo and lapatinib, so the primary question concerns a contrast across treatment periods within a single-sequence study rather than a conventional comparison of independently randomized groups. This makes the timing and structure of repeated ECG readings central to interpretation.
The study used continuous Holter monitoring and repeated triplicate ECG measurements. Averaging replicate readings and tracking QTcF at multiple post-dose times can characterize measurement patterns in detail. At the same time, a set of time-specific estimates creates questions about correlation among observations, model assumptions, and multiplicity. The registry specifies repeated-measures analysis of variance and its treatment and time terms, but does not report the covariance specification or multiplicity handling.
The endpoint is also an example of a corrected physiological measurement. QTcF applies Fridericia correction to QT, addressing the relationship between QT and heart rate. Statistical interpretation still depends on measurement quality, baseline definition, the analysis model, and the uncertainty around the treatment contrast. The registry describes these elements at a high level, while omitting the numerical endpoint results needed to assess effect size and precision.
Finally, the study illustrates why design labels and denominators matter. Allocation is recorded as NA and the design as a single group, while serious-event counts are listed under placebo and lapatinib. These counts should not be treated as if they came from separate randomized groups. The record’s design and result limitations are essential context for any statistical reading.
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 central limitation for interpretation is that the primary endpoint results are not reported in the registry record. Although the planned outcome is defined in detail and the analysis approach is described, no treatment-difference estimates, standard errors, or 90% confidence intervals are available. This prevents assessment of the direction, size, and precision of the primary contrast.
The record describes a single-sequence crossover but does not report a washout period, treatment-order assessment, or analysis of possible period or carryover effects. The planned sequence is described, but the available information does not show how those design features were assessed statistically. The number of participants with evaluable data for the primary analysis is also not reported, despite the population definition.
Further analysis details are absent: the repeated-measures covariance structure, model diagnostics, missing-data methods, sensitivity analyses, and multiplicity approach are not reported in the registry record. These matters are relevant because ECG observations are repeated over time and several time points and outcome measures are listed.
The safety information is limited to group-level participant counts and selected serious adverse-event terms. Deaths are not reported, and details such as event timing, relatedness, duration, and outcomes are not included. Because the trial is not a randomized comparison between independent groups, the listed counts do not establish a causal treatment contrast. The registry also does not report participant-level information that would clarify overlap between treatment periods.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study in Cancer Patients to Evaluate the Effect of Lapatinib on the QTc Interval — NCT01328054.
- Registry record last updated 2016-06-08; status last verified 2016-05.
- Results first posted 2016-06-08.
- 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.
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18. Record Summary
This completed Phase IV study examined repeat oral lapatinib 2000mg and placebo in participants with advanced cancer using a single-sequence crossover design. The registry lists 58 enrolled participants and describes the primary outcome as the baseline-adjusted treatment difference in QTcF at scheduled time points, analyzed with repeated-measures analysis of variance and 90% confidence intervals.
The record defines the ECG measurement and evaluable population, but does not report the primary treatment estimates, confidence intervals, or the number of participants included in the evaluable analysis. It lists serious adverse events for 0 of 57 participants in the placebo group and 4 of 58 in the lapatinib group; these counts are descriptive and are not a randomized treatment comparison. Details of multiplicity and missing-data methods are not reported in the registry record.