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 Trial of Afatinib (BIBW 2992) + Cetuximab in Advanced Solid Tumours (NCT02020577), a na phase 1 study. The primary outcome is MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib)..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02020577 |
| Phase | Phase 1 |
| Condition | Neoplasms |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 58 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
Population
Adults with advanced solid tumours were the intended population. Part A was a dose-finding cohort; Part B was planned to include cohorts with squamous non-small cell lung cancer, recurrent or metastatic squamous cell carcinoma of the head and neck, and other advanced solid tumours except sarcomas. The registry record does not report further eligibility details.
Intervention
The combination was afatinib taken once daily with cetuximab given by weekly infusion. The registry lists dose groups of afatinib 30mg or 40mg with cetuximab 250 mg/m². The record does not report the full dosing schedule or dose-escalation decisions.
Comparator
There was no separate control group: the study is recorded as single-group, with no masking and allocation listed as not applicable. The dose groups are not a randomized, like-for-like comparison, so differences between them cannot be read as controlled treatment effects.
Primary question
In the Part A dose-finding cohort, what maximum tolerated dose of afatinib in combination with cetuximab was identified using dose-limiting toxicities during the first treatment cycle? The registry defines the maximum tolerated dose as the highest dose level at which fewer than 33% of patients experience a dose-limiting toxicity during that cycle. The outcome value is not reported in the registry record.
The study was designed to address a dosing question rather than estimate a comparative treatment effect. Its stated primary endpoint concerns tolerability in the first treatment cycle, while the listed secondary outcomes include dose-limiting toxicities across treatment cycles and response measures. The record does not report the numerical results for these outcomes, so it does not establish which dose met the stated criterion or what response results were observed.
3. Trial Design
This was a Phase Ib, single-group study of afatinib in combination with cetuximab in patients with advanced solid tumours. The registry records enrollment of 58 participants, no masking, and allocation as not applicable. The listed start was 2013-12, primary completion was 2015-01, and study status is completed. The sponsor was Boehringer Ingelheim.
The brief description divides the study into Part A and Part B. Part A was intended for dose finding, including assessment of dose-limiting toxicity and the maximum tolerated dose. Part B was planned as an expansion at the maximum tolerated dose in three cohorts: squamous non-small cell lung cancer, recurrent or metastatic squamous cell carcinoma of the head and neck, and other advanced solid tumours except sarcomas. The registry record does not report how many participants entered each part or cohort, or the final dose chosen for expansion.
The recorded dose groups were afatinib 30mg with cetuximab 250 mg/m² and afatinib 40mg with cetuximab 250 mg/m². These groups do not constitute randomized treatment and control arms. The registry does not describe random assignment, and its allocation field is not applicable. Consequently, any differences between dose groups could reflect their place in dose finding, cohort composition, or other factors; the record does not support interpreting them as an unbiased comparison of treatment effects.
The primary endpoint population is defined as the dose-finding cohort treated set: patients enrolled in Part A who were documented to have taken at least one dose of study medication. That definition is specific to the primary endpoint. The analysis populations used for secondary outcomes are not reported in the registry record. The study design and endpoint description provide a framework for understanding what was intended to be assessed, but the registry does not report the primary endpoint result or the decisions made during dose escalation.
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: Uncontrolled, open label, 3+3 dose escalation (Part A) study of afatinib in combination with cetuximab, followed by an expansion phase in 3 cohorts of patients (Part B). Adverse Event (AE). CTCAE: Common Terminology Criteria for Adverse Events
Overall Study
| Stage | Afatinib 30mg+Cetuximab 250 mg/m² | Afatinib 40mg+Cetuximab 250 mg/m² |
|---|---|---|
| STARTED | 3 | 55 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 3 | 55 |
Reasons for not completing this period:
| Reason | Afatinib 30mg+Cetuximab 250 mg/m² | Afatinib 40mg+Cetuximab 250 mg/m² |
|---|---|---|
| Progressive disease | 3 | 38 |
| Other AE or clinical progression | 0 | 15 |
| Withdrawal by Subject | 0 | 1 |
| Other than stated above | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Dose finding cohort treated set: This patient set includes all patients enrolled in part A of the trial who were documented to have taken at least one dose of study medication.
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: Treated set: This patient set includes all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
| Characteristic | Unit | Afatinib 30mg+Cetuximab 250 mg/m² | Afatinib 40mg+Cetuximab 250 mg/m² | Total |
|---|---|---|---|---|
| Participants analysed | 3 | 55 | 58 | |
| Age, Continuous | Years | 63.3 (SD 7.6) | 61.0 (SD 11.4) | 61.1 (SD 11.2) |
| Sex: Female, Male: Female | Participants | 0 | 20 | 20 |
| Sex: Female, Male: Male | Participants | 3 | 35 | 38 |
6. Primary Endpoint
The registry lists the primary outcome as MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib)., measured over First 21 days treatment cycle.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | mg |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the maximum tolerated dose of afatinib in combination with cetuximab, expressed in mg and based on the number of patients with dose-limiting toxicities during the first treatment cycle. The specified timeframe is the first 21 days of treatment. The registry defines the maximum tolerated dose as the highest dose level at which fewer than 33% of patients experience a dose-limiting toxicity in that cycle.
This endpoint is used in dose-finding research to identify a dose level for further study while explicitly considering early treatment-limiting toxicity. It is not a measure of comparative efficacy. The endpoint’s interpretation depends on the dose levels tested, the number of evaluable participants at each level, how dose-limiting toxicities were defined and assessed, and the escalation decisions. The registry record does not report those operational details or the endpoint value.
The stated primary analysis population includes patients enrolled in Part A who took at least one dose of study medication. This is a treated set, not all enrolled participants irrespective of treatment exposure. The record gives the population definition but does not report the number included in the primary endpoint analysis, the number with evaluable toxicity data, or the number with dose-limiting toxicities at each dose. Therefore, the registry description identifies the intended measure and decision threshold, but it does not allow the maximum tolerated dose to be reconstructed.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central statistical feature is that the primary question is about dose selection, not about whether the combination performs better than another treatment. The registry describes a dose-finding part and planned expansion cohorts, with afatinib given alongside cetuximab. It does not identify a concurrent control group, and the study is recorded as single-group with allocation not applicable. The dose groups therefore should not be treated as randomized comparison arms.
The registry defines the maximum tolerated dose through the frequency of dose-limiting toxicity in the first 21 days: it is the highest dose level at which fewer than 33% of patients have a dose-limiting toxicity during the first treatment cycle. This is a decision rule, not a reported finding. The registry record does not state which dose level satisfied the rule, how many patients had a dose-limiting toxicity in each level, or what dose was taken forward. No primary endpoint value is reported.
The listed enrollment is 58, and the adverse-event record includes dose groups of 3 patients at risk in the 30mg afatinib group and 55 at risk in the 40mg afatinib group, as well as an all-patients group of 58. Those safety counts describe the groups in the adverse-event record; they do not provide the missing primary dose-limiting toxicity results. Serious adverse events and other adverse events are separate safety summaries, and their counts should not be substituted for the endpoint’s specifically defined dose-limiting toxicities.
Secondary outcomes named in the record include dose-limiting toxicities during all treatment cycles, recommended Phase II dose based on dose-limiting toxicity events for each study drug, best overall response, objective response, and disease control rate. The record does not report numerical results for these outcomes. It also records 9 outcome measures and 0 analyses, so the statistical interpretation cannot draw on reported analysis-level estimates, confidence intervals, or hypothesis tests.
For a dose-finding study, the amount of information at each dose level is important. The adverse-event record lists different numbers at risk in the dose groups, and the smaller group has limited descriptive information. Even when counts are available, estimates from small groups can be imprecise. No uncertainty interval for the primary endpoint or dose-specific toxicity rate is reported. The registry also does not report the dose-escalation method or whether any interim review occurred, so those procedures cannot be inferred from the stated endpoint definition alone.
Overall, the registry supports a description of the study question, dose groups, and selected safety counts, but not a conclusion about the dose ultimately selected or the observed efficacy outcomes. The intended expansion cohorts are part of the planned design description; the record does not establish the results within those cohorts. The absence of reported outcome values is a limit on interpretation, not evidence that an outcome did or did not occur.
9. Statistical Methods Explained
The statistical design is best understood as dose finding with a planned expansion, rather than as a conventional comparative trial. The primary endpoint asks which afatinib dose, when combined with cetuximab, meets a specified early-toxicity criterion. The study record describes a single-group design, no masking, and allocation as not applicable. That information rules out interpreting the listed dose groups as randomized arms with a concurrent control.
What does the maximum tolerated dose rule mean?
The registry defines the maximum tolerated dose as the highest dose level at which fewer than 33% of patients experience a dose-limiting toxicity during the first treatment cycle. In general, a threshold rule translates observed toxicity into a dose-selection decision. The rule does not by itself tell the reader which dose was selected. That requires the observed number of patients with dose-limiting toxicity, the relevant denominator at each dose level, and the dose-escalation process. These results and process details are not reported in the registry record.
The primary endpoint is framed as a number, with mg as its unit, and its assessment period is the first 21 days of treatment. The registry says the endpoint population consists of patients enrolled in Part A who took at least one dose of study medication. This definition matters because people who were enrolled but did not take study medication would not meet that stated treated-set definition. The record does not report how many participants met the endpoint population definition or how missing or incomplete toxicity observations were handled.
Why is a dose-finding result not a treatment comparison?
In general, a randomized comparison aims to separate treatment differences from differences that arise because groups contain different kinds of participants or receive care in different circumstances. This study is recorded as single-group, with no allocation and no masking. Its dose levels are part of a dose-finding sequence, not independent randomized treatment choices. Differences in observed outcomes across dose groups could be affected by dose-escalation order, group size, or participant characteristics. The record does not report an adjusted or randomized comparison, so these differences should be read descriptively.
The registry lists 3 patients at risk in the afatinib 30mg group and 55 in the afatinib 40mg group for the adverse-event summaries. Unequal group sizes are relevant when reading counts: a larger count in one group need not mean a higher event frequency. The registry also reports affected counts, but those summaries concern adverse events, not necessarily the endpoint’s dose-limiting toxicities. A dose-limiting toxicity is a protocol-defined concept; the registry record does not report its detailed criteria or how it relates to the event categories in the safety summary.
How should uncertainty be understood?
In general, a confidence interval describes a range of values compatible with data under a specified statistical procedure and conveys precision as well as an estimate. No confidence interval for the primary endpoint is reported in this registry record. The absence of an interval means that the precision of the dose-finding result cannot be assessed from the record. The endpoint value itself is also not reported, so there is no estimate to interpret.
In general, over-dispersion occurs when observed variability exceeds what a statistical model assumes. It can make standard errors and confidence intervals too small if the model fails to account for that extra variability. The registry record does not describe a model for count outcomes, report an over-dispersion assessment, or provide analysis details that would allow this issue to be evaluated. This is a general statistical consideration, not a claim about the methods used in the trial.
The record lists 9 outcome measures and 0 analyses. Outcome names alone do not reveal how measurements were summarized, what statistical tests or models were used, whether estimates were adjusted, or how uncertainty was quantified. Those analysis methods are not reported in the registry record. The listed outcomes include both toxicity-related measures and response measures, which answer different questions and should not be collapsed into a single overall claim.
What can planning calculations say?
In general, sample-size calculations are planning tools that relate a target effect, variability assumptions, significance level, and desired power to a proposed sample size. They are not evidence that a study had a particular chance of finding an effect after the results are known. The planning assumptions associated with this record describe an illustrative calculation using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a fraction of an observed effect. For time-to-event outcomes, such illustrations use total events; for other outcomes, they use participants per arm.
Those assumptions do not make this single-group dose-finding trial a two-arm randomized comparison. The registry record does not report an observed effect for a comparative endpoint or a trial-specific sample-size justification. Any planning illustration should therefore be kept separate from the study’s design and from its observed findings. It cannot be read as observed power, and it does not supply the missing dose-finding result.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 9 outcome measures, including the primary dose-finding endpoint and secondary measures related to toxicity, recommended Phase II dose, and tumour response. When a study assesses multiple outcomes, the chance of at least one apparently notable result can increase if many statistical tests are performed without an appropriate strategy. In general, multiplicity methods may control that risk or clarify which outcomes are confirmatory and which are exploratory. The registry record does not report a multiplicity strategy, an outcome hierarchy beyond identifying the primary endpoint, or analysis details for the listed outcomes.
The record reports 0 analyses. It therefore contains no analysis-level estimates or tests to assess for multiplicity. This does not establish whether analyses were performed outside the registry record; it means that their methods and results are not reported in the registry record.
Missing-data procedures are also not reported. The primary population is defined as Part A patients documented to have taken at least one dose, but the number meeting that definition and the handling of incomplete toxicity assessments are not given. The record does not report whether missing outcome values were excluded, imputed, or addressed through another approach. The populations used for the secondary outcomes are not reported either.
These omissions limit assessment of how complete and comparable the outcome data were and how strongly the findings, if reported elsewhere, would support the stated questions. They should not be interpreted as evidence that missing values or multiplicity concerns did or did not occur.
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 |
|---|---|---|---|
| Afatinib 30mg+Cetuximab 250 mg/m² | 1 | 3 | 33.3% |
| Afatinib 40mg+Cetuximab 250 mg/m² | 31 | 55 | 56.4% |
| All Patients | 32 | 58 | 55.2% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Afatinib 30mg+Cetuximab 250 mg/m² | 3 of 3 |
| Afatinib 40mg+Cetuximab 250 mg/m² | 54 of 55 |
| All Patients | 57 of 58 |
Most frequent serious adverse event terms
| Event term | Organ system | Afatinib 30mg+Cetuximab 250 mg/m² | Afatinib 40mg+Cetuximab 250 mg/m² | All Patients |
|---|---|---|---|---|
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 3 | 5 of 55 | 6 of 58 |
| Sepsis | Infections and infestations | 0 of 3 | 3 of 55 | 3 of 58 |
| Dehydration | Metabolism and nutrition disorders | 0 of 3 | 3 of 55 | 3 of 58 |
| Diarrhoea | Gastrointestinal disorders | 0 of 3 | 2 of 55 | 2 of 58 |
| Asthenia | General disorders | 0 of 3 | 2 of 55 | 2 of 58 |
| Respiratory tract infection | Infections and infestations | 0 of 3 | 2 of 55 | 2 of 58 |
| Hypercalcaemia | Metabolism and nutrition disorders | 0 of 3 | 2 of 55 | 2 of 58 |
| Hypokalaemia | Metabolism and nutrition disorders | 0 of 3 | 2 of 55 | 2 of 58 |
| Back pain | Musculoskeletal and connective tissue disorders | 0 of 3 | 2 of 55 | 2 of 58 |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | 0 of 3 | 2 of 55 | 2 of 58 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Afatinib 30mg+Cetuximab 250 mg/m² | Afatinib 40mg+Cetuximab 250 mg/m² | All Patients |
|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 1 of 3 | 35 of 55 | 36 of 58 |
| Hypomagnesaemia | Metabolism and nutrition disorders | 0 of 3 | 26 of 55 | 26 of 58 |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | 2 of 3 | 22 of 55 | 24 of 58 |
| Folliculitis | Infections and infestations | 0 of 3 | 18 of 55 | 18 of 58 |
| Paronychia | Infections and infestations | 1 of 3 | 17 of 55 | 18 of 58 |
| Asthenia | General disorders | 0 of 3 | 17 of 55 | 17 of 58 |
| Decreased appetite | Metabolism and nutrition disorders | 0 of 3 | 17 of 55 | 17 of 58 |
| Dry skin | Skin and subcutaneous tissue disorders | 2 of 3 | 14 of 55 | 16 of 58 |
| Skin fissures | Skin and subcutaneous tissue disorders | 0 of 3 | 14 of 55 | 14 of 58 |
| Stomatitis | Gastrointestinal disorders | 1 of 3 | 11 of 55 | 12 of 58 |
Serious events with the highest arm-level rate: upper limb fracture (33.3%), malignant neoplasm progression (33.3%), cognitive disorder (33.3%), sepsis (5.5%), dehydration (5.5%).
The adverse-event record gives at-risk and affected counts for the 30mg and 40mg afatinib dose groups and for all patients. For serious adverse events, the 30mg group has 3 at risk and 1 affected; the 40mg group has 55 at risk and 31 affected; and the all-patients group has 58 at risk and 32 affected. For other adverse events, the corresponding counts are 3 at risk and 3 affected, 55 at risk and 54 affected, and 58 at risk and 57 affected. These are descriptive counts, not a controlled comparison.
The registry lists upper limb fracture, malignant neoplasm progression, and cognitive disorder at 33.3% each among the top serious-event terms; it also lists sepsis and dehydration at 5.5% each, and diarrhoea at 3.6%. The record does not give additional denominator context for these term percentages in the adverse-event summary. The death count is not reported in the registry record.
Serious adverse events are not interchangeable with dose-limiting toxicities. The primary endpoint concerns dose-limiting toxicity during the first treatment cycle, while the safety summary describes serious and other adverse events. The registry does not report which events met the protocol definition of dose-limiting toxicity, nor does it provide timing or event-level attribution in the summary. These counts therefore describe reported safety categories but do not determine the primary dose-finding result.
12. What the Result Does, and Does Not, Mean
The registry record establishes that the study was designed to examine afatinib dose finding in combination with cetuximab and to plan expansion cohorts at the maximum tolerated dose. It defines the primary endpoint as a dose-selection measure based on dose-limiting toxicity during the first treatment cycle. It also records the combination regimen, the dose groups appearing in safety summaries, and counts of participants affected by serious and other adverse events.
The record does not report the maximum tolerated dose result, dose-specific counts of primary endpoint dose-limiting toxicities, or numerical results for the response outcomes. It therefore cannot establish from the registry information which dose met the threshold, which dose was recommended for further study, or what tumour responses were observed. The absence of these results should not be interpreted as a favorable or unfavorable finding.
The study was single-group and did not include a randomized control group. The recorded dose groups are not a like-for-like comparison, so differences between them do not provide a reliable estimate of what would have happened under an alternative treatment. The listed safety counts can be described, but they do not by themselves establish comparative safety or efficacy.
More generally, a trial designed to identify a dose addresses a different statistical question from a trial designed to estimate a treatment effect. Dose finding focuses on a stated toxicity rule and the information gathered at tested dose levels. A treatment comparison would require a suitable comparator and a specified comparative analysis. The registry record does not report such an analysis. Its design description and safety summaries are useful for understanding the study’s scope, but they are not a substitute for the missing endpoint results, analysis methods, and uncertainty estimates.
13. Why This Trial Matters Statistically
This trial illustrates an important distinction in clinical-trial statistics: a dose-finding study and a comparative efficacy study do not answer the same question. The primary endpoint is a dose-selection rule based on early dose-limiting toxicity, not a direct comparison of treatment benefit against a control. The endpoint’s meaning depends on both the specified threshold and the observed toxicity information at each dose level.
The record also shows why design labels matter. A single-group study with allocation not applicable does not create randomized treatment arms merely because more than one dose group appears in the safety summary. Group sizes differ, and the record does not report randomization or an adjusted comparison. Descriptive differences between the groups should not be interpreted as causal effects of dose.
Another statistical lesson is that an endpoint definition is not an endpoint result. The registry specifies the first-cycle timeframe, the treated-set population, and the less-than-33% criterion, but does not report the maximum tolerated dose or the dose-limiting toxicity counts needed to evaluate that criterion. A precise definition makes the question clear; it cannot replace the numerical outcome.
Finally, the registry’s safety counts are informative as descriptive reporting but are distinct from the primary endpoint. Serious adverse events, other adverse events, and dose-limiting toxicities may use different definitions and timeframes. Keeping those measures separate prevents a safety summary from being mistaken for the result of the dose-selection rule. The missing analyses and outcome values also demonstrate why registry design details alone cannot support conclusions about efficacy or the dose ultimately selected.
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 main limitation for statistical interpretation is that the registry record does not report the primary endpoint result. Although the endpoint definition and its first-cycle timeframe are stated, the record gives no maximum tolerated dose value and no dose-specific dose-limiting toxicity counts. The dose-escalation method, dose-limiting toxicity criteria, and any dose-selection decisions are also not reported.
The study has no concurrent randomized control group. Its dose groups should not be treated as comparable intervention and control arms, particularly because their at-risk counts differ and the record does not describe randomization. The registry also does not report adjustment methods that could address differences between dose groups.
Outcome reporting is incomplete for assessing efficacy and precision. Response measures are listed, but their numerical results, uncertainty estimates, and analysis methods are not reported. The registry records 9 outcome measures and 0 analyses. The primary treated-set population is defined, but the number analyzed and the handling of missing or incomplete observations are not reported. The analysis populations for secondary outcomes are not reported either.
The safety summaries provide counts for serious and other adverse events, but they do not identify which events met the dose-limiting toxicity definition or give the timing and assessment details needed to connect them to the primary endpoint. The death count is not reported. These limitations restrict what can be concluded from the registry record and do not establish whether additional information exists elsewhere.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Trial of Afatinib (BIBW 2992) + Cetuximab in Advanced Solid Tumours — NCT02020577.
- Registry record last updated 2017-06-22; status last verified 2017-05.
- Results first posted 2016-02-12.
- 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
NCT02020577 is a completed Phase Ib, single-group study of afatinib combined with cetuximab in advanced solid tumours, sponsored by Boehringer Ingelheim. The registry lists enrollment of 58, a start in 2013-12, and primary completion in 2015-01. The study description has a dose-finding part and planned expansion cohorts.
The primary endpoint concerns the maximum tolerated dose of afatinib based on dose-limiting toxicity during the first 21 days. The registry defines the dose threshold but does not report the endpoint result. It lists secondary toxicity and response outcomes but gives no numerical outcome analyses. Safety summaries report serious and other adverse-event counts by dose group and for all patients. The record does not describe a randomized comparison, analysis methods, missing-data handling, or a multiplicity strategy.