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 Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC (NCT04648033), a non-randomized phase 1 study. The primary outcome is Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04648033 |
| Phase | Phase 1 |
| Condition | Locally Advanced Non-Small Cell Lung Cancer |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 21 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Oxford |
| Results posted | Yes |
2. Clinical Question
Population
Participants with locally advanced non-small cell lung cancer receiving radical concurrent chemoradiotherapy. The registry record describes an intended group of twenty evaluable participants recruited at three centres and an enrollment of 21.
Intervention
Atovaquone oral suspension alongside standard of care chemotherapy and radiotherapy. Atovaquone was taken during an initial run-in period and then continued during chemoradiotherapy. The four listed dose levels were 450 mg, 600 mg, 675 mg and 750 mg, each given twice daily.
Comparator
There was no separate control group. The study was non-randomized and used a single-group design. Dose levels were assigned through a time-to-event continual reassessment method that was described as taking toxicity information into account.
Primary question
How many dose-limiting toxicities occurred during the stated observation period, and what maximum tolerated dose level—and corresponding recommended phase II dose—could be identified for atovaquone given with radical concurrent chemoradiotherapy? The registry describes the target dose as one associated with no more than 48% dose-limiting toxicity. It does not report the primary outcome result or the selected dose.
This is a dose-finding question, not a randomized comparison of atovaquone against chemoradiotherapy alone. The stated objective is to assess tolerability while combining atovaquone with the existing treatment regimen. The trial also listed secondary measures concerning adverse-event severity, tumour hypoxia, plasma miR-210, tumour response, and the ability to derive a hypoxia metagene signature from archival tumour material. The registry record does not report numerical results for these secondary measures.
3. Trial Design
The trial is registered as NCT04648033 and is titled “Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC.” Its official title describes a phase I trial of atovaquone with radical concurrent chemoradiotherapy in locally advanced non-small cell lung cancer. The sponsor is the University of Oxford. The registry lists the study as completed, with a start date of 2020-12-07 and a primary completion date of 2023-10-02.
This was an open-label, non-randomized, single-group study. There was no masking and no parallel control arm. The record lists 21 participants enrolled, while the brief summary describes recruitment of twenty evaluable participants at three centres. Enrollment and the intended number of evaluable participants are different descriptions; the registry record does not state how many participants ultimately contributed to the primary endpoint.
Atovaquone was administered with standard of care chemotherapy and radiotherapy. The listed dose levels were 450 mg twice daily, 600 mg twice daily, 675 mg twice daily, and 750 mg twice daily. The arm descriptions state that participants began with an initial run-in period of 2 weeks, with a permitted variation of 7 days, and then continued atovaquone during standard of care chemoradiotherapy. They also describe dose assignment using a time-to-event continual reassessment method, with toxicity information to date informing allocation.
The primary outcome was the number of dose-limiting toxicities from the first atovaquone dose to the 3-month follow-up visit, with the timeframe described as up to 25 weeks. The stated aim was to identify the maximum tolerated dose and recommended phase II dose. The registry record does not report additional details about eligibility criteria, the operational definition of a dose-limiting toxicity, dose-allocation boundaries, or the final dose-finding decision.
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.
Overall Study
| Stage | Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT |
|---|---|---|---|---|
| STARTED | 3 | 2 | 1 | 15 |
| COMPLETED | 3 | 2 | 1 | 15 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
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 | Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 3 | 2 | 1 | 15 | 21 | |
| Age, Continuous | Years | 67.3 (SD 17.7) | 48.0 (SD 9.9) | 65.0 (SD NA) | 65.2 (SD 16.4) | 63.9 (SD 10.7) |
| Sex: Female, Male: Female | Participants | 0 | 1 | 0 | 6 | 7 |
| Sex: Female, Male: Male | Participants | 3 | 1 | 1 | 9 | 14 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 3 | 2 | 1 | 9 | 15 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 6 | 6 |
| Smoking status: Never smoked | Participants | 1 | 1 | 0 | 0 | 2 |
| Smoking status: Ex-smoker | Participants | 2 | 0 | 1 | 13 | 16 |
| Smoking status: Current smoker | Participants | 0 | 1 | 0 | 2 | 3 |
| Non-small cell lung cancer sub-type: Adenocarcinoma | Participants | 3 | 1 | 0 | 4 | 8 |
| Non-small cell lung cancer sub-type: Squamous cell carcinoma | Participants | 0 | 1 | 1 | 11 | 13 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Dose Limiting Toxicities in Patients Taking Atovaquone in Combination With Radical Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer., measured over From first dose of atovaquone to 3-month follow up visit (up to 25 weeks).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Dose Limiting Toxicities (DLTs) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the number of dose-limiting toxicities among participants taking atovaquone with radical concurrent chemoradiotherapy. The registry specifies that events are considered from the first atovaquone dose through the 3-month follow-up visit, described as up to 25 weeks. It frames the endpoint as a way to determine the maximum tolerated dose level and the corresponding recommended phase II dose.
In a dose-finding study, counting dose-limiting toxicities helps assess whether treatment-related toxicity at a dose level is consistent with the level of risk the study is designed to target. The registry states that the intended dose is associated with no more than 48% dose-limiting toxicity. This is the target toxicity level in the study description, not a reported observed toxicity rate. The actual number of primary endpoint events, the number of participants assessed for this endpoint, and the selected dose are not reported in the registry record.
The primary endpoint is distinct from the broader adverse-event summaries. A serious adverse event is not necessarily a dose-limiting toxicity: the registry’s primary endpoint requires the study’s dose-limiting-toxicity definition, and the record does not give that definition. Nor does the primary endpoint alone describe tumour response or changes in hypoxia-related measures. Those were listed as separate secondary outcomes. Without the primary endpoint result and its assessment details, the registry record cannot establish how the observed toxicity experience informed dose selection.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes a completed phase I dose-finding study, but completion status is not itself a report of the endpoint findings. The main statistical question was whether a dose level of atovaquone could be selected for use with concurrent chemoradiotherapy based on dose-limiting toxicities. The record states the intended target toxicity level, but does not report the primary endpoint count, the number of assessed participants, the estimated toxicity at each dose, or the final maximum tolerated dose. Those central results are not reported in the registry record.
The adverse-event information is presented by dose level. The number of participants at risk for serious adverse events and the number affected were 3 and 2 at 450 mg, 2 and 1 at 600 mg, 1 and 0 at 675 mg, and 15 and 7 at 750 mg. For other adverse events, the corresponding at-risk and affected counts were 3 and 3, 2 and 2, 1 and 1, and 15 and 15. The registry reports 0 deaths in each of the first three dose groups and 2 deaths in the 750 mg group. These are descriptive summaries; they do not provide the dose-limiting-toxicity endpoint result.
The groups are markedly different in size, and dose assignment was non-randomized. The dose levels therefore should not be treated as though they were concurrent randomized groups. Participants receiving different doses may differ in when or why they were assigned to those doses, and the statistical design explicitly used toxicity information to guide allocation. The observed counts cannot isolate a causal effect of dose, or distinguish dose-related events from events associated with the disease, chemoradiotherapy, or other factors.
The serious adverse-event terms listed include vomiting, ataxia, angina pectoris, acute kidney injury, pneumonitis, and diarrhoea, each with a registry-reported percentage. These percentages describe the posted serious-event information, but the record does not provide enough detail in the listed terms to treat them as risks among all enrolled participants or as dose-limiting toxicity rates. Event counts, affected-participant counts, and the primary dose-limiting-toxicity outcome are not interchangeable.
The registry also names secondary outcomes involving tumour hypoxia, plasma miR-210, archival tumour samples, and objective tumour response. Numerical results for those outcomes are not reported in the registry record. Therefore, the available information supports a description of the trial’s design and some adverse-event counts, but not a conclusion about the selected dose, the precision of the primary estimate, or the other secondary endpoints.
9. Statistical Methods Explained
What does the dose-finding method do?
General statistical explanation: the time-to-event continual reassessment method is an adaptive dose-finding approach. Rather than assigning everyone to fixed dose groups under a conventional randomized design, a method of this type can use accumulating toxicity information to guide subsequent dose assignment. The registry brief describes this trial as using TiTE-CRM to determine the maximum tolerated dose, and the arm descriptions say that dose assignment took account of toxicity data to date. The registry record does not report the model specification, the toxicity observation window used for each decision, the exact allocation algorithm, or its operating characteristics.
The time-to-event element is generally relevant when an outcome such as toxicity may occur after treatment starts and participants have different lengths of follow-up. Methods in this family can make use of partial follow-up information rather than treating every participant without an event to date as though their observation were complete. That is a general description, not confirmation of the exact implementation in this trial. The registry record does not describe how incomplete toxicity follow-up was handled in dose assignment.
Why does the endpoint focus on toxicity?
General statistical explanation: early-phase dose-finding studies often aim to select a dose for later study, rather than to estimate a treatment effect against a control group. A toxicity target defines the level of dose-limiting toxicity the design is intended to tolerate when selecting a dose. In this record, that target is stated as no more than 48%. It is a design target, not an observed result. The registry record does not report how the study translated accumulated toxicity information into the final dose decision.
The primary endpoint is a count of dose-limiting toxicities over a specified period. A count depends on both the number of participants observed and the amount of follow-up available. For interpretation, it is important to know the event definition, whether each participant could contribute more than one event, the rules for attributing events, and how incomplete follow-up was handled. Those details are not reported in the registry record. The posted adverse-event summaries should therefore not be substituted for the primary endpoint.
What can the adverse-event summaries tell readers?
General statistical explanation: a count of participants with at least one event is different from a count of all events. A participant can experience more than one adverse event, and terms listed for serious events may describe events rather than unique people unless the record specifies otherwise. The registry reports at-risk and affected counts by dose group, as well as selected serious-event terms and percentages. It does not give further detail on the counting rules for those terms in the information presented. The dose-group counts are descriptive and do not by themselves support a controlled comparison.
Unequal group sizes affect how stable descriptive summaries may be. A count from a group with few participants can change substantially with the experience of an individual participant. This general consideration is especially relevant when the group sizes listed in the record vary from one participant at a dose level to 15 at another. These counts should not be interpreted as precise dose-specific rates without the relevant denominator, endpoint definition, follow-up, and uncertainty information.
General statistical explanation: over-dispersion occurs when variation in count data is greater than expected under a simple count model. It can arise when participants have different underlying risks or when event counts cluster. The registry’s primary outcome is classified as a count, but it gives no dispersion estimate or model results. There is therefore no basis in the registry record to describe whether over-dispersion was assessed or how it affected inference.
What do confidence intervals and p-values usually add?
General statistical explanation: a confidence interval describes the range of values compatible with a statistical estimate under the assumptions of the analysis. Its width communicates precision; a broad interval indicates substantial uncertainty, while a narrow interval indicates greater precision. A p-value, when used, measures how incompatible the observed data are with a stated null hypothesis under the analysis assumptions. Neither measure establishes clinical importance or resolves bias from a non-randomized design. The registry record does not report a confidence interval or p-value for the primary endpoint.
Because this is a dose-finding study without a control arm, a conventional treatment-versus-control effect estimate is not the central estimand described in the record. The primary objective is dose selection based on toxicity. No comparative estimate, inferential interval, or formal test for a treatment effect is reported in the registry record.
How should sample-size illustrations be read?
General statistical explanation: a sample-size calculation is a planning tool, not a summary of what happened in a trial. The record’s sample-size assumptions describe an illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. For time-to-event settings, the illustration concerns total events; for other settings, it concerns participants per arm. These assumptions do not make this single-group dose-finding trial a two-arm randomized comparison and do not establish the power achieved in the enrolled participants.
General statistical explanation: observed power is not a substitute for reporting the endpoint estimate and its uncertainty. A planning illustration based on an observed effect cannot show that a trial had a particular probability of detecting an effect after the data were collected. No numeric sample-size illustration or primary effect estimate is described in the registry record. The record does not report a sample-size justification specific to the TiTE-CRM dose-finding design.
Overall, the method description establishes that toxicity-informed dose allocation was planned, but not the precise analysis used to arrive at a dose recommendation. The registry record does not report the dose-limiting-toxicity event definition, final analysis set, missing-data handling, model estimates, or dose-selection result. Readers should distinguish this limited methodological description from a complete statistical analysis plan.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists one primary outcome and several secondary outcomes. These secondary measures cover worst adverse-event severity by dose, the derivation of a hypoxia metagene signature from archival tumour samples, baseline tumour hypoxia, baseline plasma miR-210, changes in those biomarkers after the initial atovaquone period, and objective tumour response. Listing multiple outcomes raises a general multiplicity issue: when many outcomes are tested or interpreted, the chance of emphasizing a chance finding can increase. The registry record does not report a multiplicity adjustment, a hierarchy for testing secondary outcomes, or a prespecified approach to interpreting multiple comparisons.
The registry record does not report numerical results for the listed secondary endpoints. It also does not specify how many participants had usable measurements for each endpoint, whether all enrolled participants were included in each analysis, or how missing measurements were handled. The stated aim to recruit twenty evaluable participants does not establish the number assessed for any particular endpoint. Enrollment was 21, but the record does not explain the relationship between enrollment and endpoint-specific analysis populations.
Missing data can affect interpretation when the probability of missingness is related to outcomes, treatment exposure, or participant characteristics. General statistical explanation: complete-case analyses may not represent all enrolled participants if those with available measurements differ systematically from those without them. The registry record does not state whether such an approach or another missing-data method was used.
The record does not report interim analyses, stopping rules, or a full statistical analysis plan. It describes toxicity-informed dose allocation, but the operational details and final analysis population are not reported in the registry record. Without those details, it is not possible to assess how endpoint multiplicity, incomplete data, or adaptive allocation affected the reported inference.
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 |
|---|---|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 2 | 3 | 66.7% |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 1 | 2 | 50.0% |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 0 | 1 | 0.0% |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 7 | 15 | 46.7% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 0 of 3 |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 0 of 2 |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 0 of 1 |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 2 of 15 |
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 |
|---|---|
| Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | 3 of 3 |
| Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | 2 of 2 |
| Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | 1 of 1 |
| Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT | 15 of 15 |
Most frequent serious adverse event terms
| Event term | Organ system | Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT |
|---|---|---|---|---|---|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | 0 of 3 | 0 of 2 | 0 of 1 | 2 of 15 |
| Diarrhoea | Gastrointestinal disorders | 0 of 3 | 0 of 2 | 0 of 1 | 2 of 15 |
| Ataxia | Nervous system disorders | 1 of 3 | 0 of 2 | 0 of 1 | 0 of 15 |
| Angina pectoris | Cardiac disorders | 1 of 3 | 0 of 2 | 0 of 1 | 0 of 15 |
| Acute kidney injury | Renal and urinary disorders | 1 of 3 | 0 of 2 | 0 of 1 | 0 of 15 |
| Vomiting | Gastrointestinal disorders | 0 of 3 | 1 of 2 | 0 of 1 | 0 of 15 |
| Hyperglycaemia | Metabolism and nutrition disorders | 0 of 3 | 0 of 2 | 0 of 1 | 1 of 15 |
| Pneumonia | Infections and infestations | 0 of 3 | 0 of 2 | 0 of 1 | 1 of 15 |
| Chest pain | General disorders | 0 of 3 | 0 of 2 | 0 of 1 | 1 of 15 |
| Inflammatory bowel disease | Gastrointestinal disorders | 0 of 3 | 0 of 2 | 0 of 1 | 1 of 15 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Dose Level 1 - 450 mg BD Atovaquone + Concurrent CRT | Dose Level 2 - 600 mg BD Atovaquone + Concurrent CRT | Dose Level 3 - 675 mg BD Atovaquone + Concurrent CRT | Dose Level 4 - 750 mg BD Atovaquone + Concurrent CRT |
|---|---|---|---|---|---|
| Gastrointestinal Disorders | Gastrointestinal disorders | 3 of 3 | 2 of 2 | 1 of 1 | 14 of 15 |
| General Disorders & Administration Site Conditions | General disorders | 3 of 3 | 2 of 2 | 1 of 1 | 11 of 15 |
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | 2 of 3 | 0 of 2 | 0 of 1 | 11 of 15 |
| Nervous System Disorders | Nervous system disorders | 2 of 3 | 1 of 2 | 0 of 1 | 9 of 15 |
| Metabolism & Nutrition Disorders | Metabolism and nutrition disorders | 1 of 3 | 1 of 2 | 0 of 1 | 8 of 15 |
| Infections & Infestations | Infections and infestations | 0 of 3 | 0 of 2 | 0 of 1 | 8 of 15 |
| Musculoskeletal & Connective Tissue Disorders | Musculoskeletal and connective tissue disorders | 2 of 3 | 1 of 2 | 0 of 1 | 3 of 15 |
| Psychiatric disorders | Psychiatric disorders | 0 of 3 | 0 of 2 | 0 of 1 | 6 of 15 |
| Skin and subcutaneous tissue disorders | Skin and subcutaneous tissue disorders | 2 of 3 | 0 of 2 | 0 of 1 | 4 of 15 |
| Blood & Lymphatic System Disorders | Blood and lymphatic system disorders | 1 of 3 | 1 of 2 | 0 of 1 | 3 of 15 |
Serious events with the highest arm-level rate: vomiting (50.0%), ataxia (33.3%), angina pectoris (33.3%), acute kidney injury (33.3%), pneumonitis (13.3%).
The adverse-event summaries give counts by atovaquone dose level. For serious adverse events, the registry lists 3 participants at risk and 2 affected at 450 mg, 2 at risk and 1 affected at 600 mg, 1 at risk and 0 affected at 675 mg, and 15 at risk and 7 affected at 750 mg. For other adverse events, it lists 3 at risk and 3 affected, 2 and 2, 1 and 1, and 15 and 15, respectively. The registry reports 0 deaths in each of the first three dose groups and 2 deaths in the 750 mg group.
These are descriptive counts, not results from randomized dose comparisons. The number of participants differs across groups, and the study was non-randomized with dose assignment guided by toxicity information. The counts do not establish that a dose caused an event, and the record does not provide a comparison that separates the effects of atovaquone from those of chemoradiotherapy, underlying illness, or other causes.
The registry also lists serious-event terms, including vomiting at 50.0%, ataxia at 33.3%, angina pectoris at 33.3%, acute kidney injury at 33.3%, pneumonitis at 13.3%, and diarrhoea at 13.3%. These terms and percentages do not replace the primary dose-limiting-toxicity outcome. The event definitions, attribution rules, and relationship of the percentages to unique participants are not reported in the registry record. Serious adverse events and dose-limiting toxicities are related but distinct concepts.
12. What the Result Does, and Does Not, Mean
The record establishes that a phase I, open-label, non-randomized, single-group study of atovaquone with radical concurrent chemoradiotherapy was completed. Its stated primary aim was to identify a maximum tolerated dose and recommended phase II dose using dose-limiting toxicity, with a target toxicity level of no more than 48%. The record also reports adverse-event counts by dose level and names several serious-event terms.
Those details do not establish which dose was selected, how many dose-limiting toxicities occurred, or whether the target toxicity level was met. The primary outcome result and final dose recommendation are not reported in the registry record. Completion status does not fill that gap. Nor do the adverse-event summaries provide a substitute, because serious adverse events are not necessarily dose-limiting toxicities and the registry does not report the relevant endpoint definition or a direct mapping between these summaries.
The results cannot be interpreted as a randomized comparison between dose levels or against chemoradiotherapy without atovaquone. Dose allocation was non-randomized and informed by toxicity data, and the group sizes were unequal. The observed counts therefore describe the registry’s dose-group summaries but do not establish causal effects of dose or treatment.
The trial also planned to examine tumour hypoxia, plasma miR-210, archival tumour material, and objective tumour response. Numerical results for these secondary endpoints are not reported in the registry record. Accordingly, the listed objectives should not be mistaken for evidence that a biomarker changed or that tumour response occurred.
General statistical explanation: a dose-finding study can provide useful information for planning later research, but the strength of any inference depends on the endpoint data, follow-up, analysis methods, and uncertainty estimates. The record does not provide enough primary-result information to judge the precision of the dose-selection decision. No treatment recommendation follows from these registry summaries.
13. Why This Trial Matters Statistically
Statistically, the trial illustrates a design whose purpose differs from that of a conventional randomized efficacy study. Its central objective was dose selection based on toxicity rather than estimation of a treatment-versus-control effect. The registry describes dose assignment through a time-to-event continual reassessment method, with toxicity information to date informing allocation. That makes clear why dose groups should not be read as independent randomized arms.
The design also highlights the importance of distinguishing the target toxicity level from the observed endpoint. The record specifies a target of no more than 48% dose-limiting toxicity, but does not report the number of dose-limiting toxicities or the dose selected. A target defines the intended decision criterion; it is not evidence that the criterion was achieved.
The available adverse-event counts also show why denominators and allocation processes matter. Group sizes range from one participant to 15 participants, and the allocation was non-randomized. A raw count can look different simply because groups differ in size, while adaptive assignment means observed groups may reflect earlier toxicity information. Careful reporting of uncertainty, follow-up, event definitions, and the final decision rule is essential for readers to evaluate a dose-finding result.
More broadly, the registry lists clinical and biomarker outcomes that could be relevant to later research, but does not report their numerical results. Statistical interpretation depends not only on a trial’s objectives and design but also on complete outcome reporting. For this record, the design can be described, and some safety summaries can be read descriptively, while the primary dose-selection conclusion remains unavailable.
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.
Several trial-specific limitations restrict interpretation of the registry record. First, the primary outcome is a count of dose-limiting toxicities, but the registry record does not report the observed count, the number of participants assessed, a dose-specific estimate, or the final maximum tolerated dose. It also does not give the operational definition of a dose-limiting toxicity. Without these elements, the main objective cannot be evaluated from the record.
Second, enrollment was 21, while the brief summary described twenty evaluable participants as the recruitment goal. The record does not explain how many participants were evaluable, how many completed the relevant follow-up, or whether the primary analysis included all enrolled participants. It does not report endpoint-specific missingness or its handling.
Third, the design was non-randomized and single-group, with dose allocation guided by accumulating toxicity information. This is appropriate to recognize as a dose-finding design, but it means the dose-group adverse-event counts are not like-for-like controlled comparisons. The group sizes are unequal, and the registry does not report uncertainty intervals or details needed to assess dose-specific precision.
Fourth, important analytic details are not reported in the registry record, including the full dose-allocation model, the toxicity observation rules used by that model, interim decision procedures, a sample-size justification for the dose-finding objective, and the final analysis population. The stated sample-size assumptions for planning illustrations concern a normal approximation and equal allocation between two arms; they should not be read as the design or observed power of this single-group trial.
Finally, numerical results for the secondary outcomes are not reported. The selected serious-event terms do not supply the missing primary endpoint and may not map directly to dose-limiting toxicities. These reporting gaps leave the primary dose-selection outcome and the biomarker and tumour-response findings unresolved in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Atovaquone With Radical ChemorADIotherapy in Locally Advanced NSCLC — NCT04648033.
- Registry record last updated 2026-01-29; status last verified 2023-05.
- Results first posted 2024-11-25.
- 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
NCT04648033 is a completed phase I, open-label, non-randomized, single-group trial sponsored by the University of Oxford. It studied atovaquone oral suspension with standard of care chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. Enrollment was 21, and the brief summary described a goal of twenty evaluable participants at three centres.
Atovaquone was listed at four twice-daily dose levels: 450 mg, 600 mg, 675 mg, and 750 mg. The primary objective was to identify a maximum tolerated dose and recommended phase II dose using dose-limiting toxicities, with a target toxicity level of no more than 48%. The primary endpoint timeframe ran from the first atovaquone dose to the 3-month follow-up visit, described as up to 25 weeks.
The registry reports adverse-event counts by dose group, but the primary endpoint result, selected dose, and numerical results for the secondary outcomes are not reported in the registry record. The non-randomized design and unequal dose-group sizes mean the adverse-event counts are descriptive rather than controlled dose comparisons.