Safety and Efficacy of Nivolumab in Treating Oral Proliferative Verrucous Leukoplakia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Nivolumab in Treating Oral Proliferative Verrucous Leukoplakia (NCT03692325), a na phase 2 study. The primary outcome is Best Overall Response Rate (BORR).

2. Clinical Question

3. Trial Design

This completed phase 2 study evaluated nivolumab in a single group of participants with oral proliferative verrucous leukoplakia. The registry lists Dana-Farber Cancer Institute as sponsor and records enrollment as 33. Allocation is listed as NA, masking as none, and the study model as single group. There was no like-for-like control comparison, so the design is descriptive rather than a randomized estimate of a treatment contrast.

Nivolumab was administered by IV infusion on Day 1 of each 28-day cycle. Treatment was to continue for a maximum of 4 cycles, or until unacceptable toxicity or withdrawal of consent. The registry records a start date of 2018-12-05, a primary completion date of 2022-09-01, and a completed status. Participants were followed up to 164 days for the primary outcome.

The primary outcome was Best Overall Response Rate (BORR), defined as the percentage of participants achieving complete response or partial response. Secondary outcomes listed in the record include quality-of-life score change, toxicity rates, time to the next surgery for a head and neck malignancy, cancer-free survival at 2 years, overall survival at 2 years, and PD-L1 combined positive scores. Numerical results for these outcomes are not reported in the registry record. Eligibility details, baseline characteristics, treatment adherence, and reasons for discontinuation are also not reported in the registry record.

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

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Best Overall Response Rate (BORR), measured over Participants were followed up to 164 days..

Best Overall Response Rate (BORR) is the percentage of participants whose best recorded response was complete response (CR) or partial response (PR). The registry says the best response was identified from study registration until the first disease progression or diagnosis of invasive OSCC. Its response assessment combines measurement and histology, using composite scores matched to a response grid. The stated categories are CR, a decrease of >80% or more; PR, a decrease of 40-80%; stable disease (SD), neither PR nor progressive disease (PD); and PD, an increase of 10% or more. For PD, the reference is the smallest measurements recorded since treatment started.

A best-response endpoint captures the most favorable qualifying response recorded over the specified assessment period, rather than change at one isolated assessment. It can therefore describe whether participants met the registry's response criteria during treatment. It does not, by itself, describe how long a response lasted or establish what would have happened without treatment. The registry identifies BORR as a percentage and specifies a 95% confidence interval, but neither the observed percentage nor its interval is reported in the registry record. Consequently, the actual response rate and its precision cannot be evaluated from the information recorded.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary response outcome at the participant level: a participant either achieved CR or PR as the best overall response, or did not meet that combined responder definition. The registry expresses the outcome as a percentage of participants and specifies a 95% confidence interval. The estimate and interval themselves are not reported in the registry record.

What does a confidence interval communicate?

In general, a confidence interval presents a range of values compatible with the observed data under a statistical procedure and its assumptions. It describes uncertainty in an estimate; it is not a range containing a known fixed percentage of individual participant responses. A point estimate alone can be difficult to interpret because it does not show how much uncertainty accompanies it. The stated 95% confidence level describes a property of the interval-generating procedure under repeated use and its assumptions, not a guarantee about the result in this particular study.

For a percentage based on a binary outcome, precision depends in part on how many participants contribute usable outcome information and on the observed distribution of responses. The registry enrollment is 33, but the analysis denominator, analysis population, and missing-outcome handling are not reported in the registry record. Enrollment therefore should not automatically be treated as the denominator for the BORR estimate. Without the numerical estimate, interval, and denominator, neither the response percentage nor its precision can be reconstructed from the registry information.

How should the response categories be understood?

The registry defines best overall response using composite scores based on both measurement and histology. It lists CR as a decrease of >80% or more, PR as a decrease of 40-80%, SD as neither PR nor PD, and PD as an increase of 10% or more. The reference for progressive disease is the smallest measurements recorded since treatment started. These are the registry's stated criteria; additional details on assessment procedures, adjudication, assessor training, or handling of borderline scores are not reported in the registry record.

Because the primary endpoint combines CR and PR, BORR is not a measure of complete response alone. It also does not directly describe response duration, changes in symptoms, quality of life, or survival. Those are distinct concepts and some related outcomes are listed separately as secondary outcomes. The registry does not report the primary endpoint's observed response categories or the numerical results for those secondary outcomes in the record information.

What does the single-group design allow?

A single-group study can describe outcomes observed among participants who received the study intervention. Without a comparator arm, it cannot estimate a randomized between-group treatment contrast. General statistical interpretation: a comparison with a concurrent control can help account for factors that affect both groups, whereas an uncontrolled outcome rate cannot by itself distinguish an intervention-associated outcome from other influences. The registry lists allocation as NA and masking as none, and explicitly indicates that the arms are not a like-for-like control comparison. No adjusted comparative analysis is reported in the registry record.

Best overall response also depends on assessment over time. The registry states that response was recorded from study registration until first disease progression or diagnosis of invasive OSCC, and that participants were followed up to 164 days for the primary outcome. The record does not describe the assessment schedule, the number of assessments, or how an assessment that was unavailable would affect classification. Those details matter because the opportunity to observe a best response can depend on follow-up and evaluability.

What do the planning assumptions mean?

The record describes a planning illustration based on a stated fraction of the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is a hypothetical planning framework, not the design of this single-group study and not observed power. The record does not report a trial-specific sample-size justification. No numerical planning results are included in the information, so no required sample size can be stated.

General statistical explanation: a planning calculation estimates what study size might be needed to detect a prespecified effect under stated assumptions. Such an illustration depends on the effect used, the significance level, allocation, and the statistical approximation. It should not be read as evidence that a study had a particular probability of finding an effect after its data were collected. The registry's planning description specifically says that the illustration is computed from the observed effect; it does not establish that this was the prospective basis for the study's enrollment.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Nivolumab")
n      <- c(33)
events <- c(12)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Nivolumab  33  12  36.4  20.4  54.9  22.2  53.4  22.2  53.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists BORR as the primary outcome and also identifies secondary outcomes, including quality-of-life score change, grade 1/2 and grade 3/4 toxicity rates, time to the next surgery for a head and neck malignancy, cancer-free survival at 2 years, 2-year overall survival, and PD-L1 combined positive scores. It records 8 outcome measures and 1 analysis. Those entries alone do not explain how the analyses were prioritized or how the chance of false-positive findings across multiple outcomes was handled.

The statistical plan for multiplicity, including any adjustment or hierarchy among outcomes, is not reported in the registry record. The record also does not report whether analyses were prespecified in a protocol or statistical analysis plan, whether interim analyses were conducted, or whether any outcomes or analyses changed over time. These details should not be inferred from the outcome list or the number of analyses recorded.

Missing-data methods and analysis populations are likewise not reported in the registry record. The record does not specify who was included in the BORR denominator, how participants without an evaluable response were treated, whether withdrawals were included, or how incomplete follow-up affected outcome classification. Enrollment of 33 does not establish the number analyzed for the primary endpoint. The registry also does not describe sensitivity analyses for missing outcomes.

These omissions limit interpretation of both the primary estimate and any secondary findings. For example, multiplicity procedures affect how evidence across several outcomes is assessed, while analysis-population and missing-data choices can affect the estimated response percentage. With neither numerical outcome results nor these analysis details reported, the registry record does not support reconstruction of the statistical analysis or evaluation of its robustness.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperglycemia (6.1%), atrial fibrillation (3.0%), atrial flutter (3.0%), chest pain - cardiac (3.0%), endocrine disorders - other, specify (3.0%).

For the nivolumab group, the registry lists 33 participants at risk for serious adverse events and 6 participants affected. For other adverse events, it lists 33 at risk and 33 affected. The record lists deaths as 0. These are descriptive safety figures for the study group, not a comparison against an untreated or alternative-treatment group.

The serious adverse-event terms listed with percentages are Hyperglycemia, 6.1%; Atrial fibrillation, 3.0%; Atrial flutter, 3.0%; Chest pain - cardiac, 3.0%; Endocrine disorders - Other, specify, 3.0%; and Hepatitis viral, 3.0%. These entries identify reported terms and percentages, but the registry information does not provide further event-level context here, such as timing, duration, recurrence, or attribution. The percentages should not be combined or treated as mutually exclusive categories.

General interpretation: adverse-event summaries describe events recorded under the study's reporting procedures. They do not, on their own, establish that the study intervention caused an event. The record does not report a comparator, and it does not give details about how serious events were assessed or whether all events were considered related to nivolumab. The counts should therefore be read as descriptive observations in the enrolled group, not as comparative risk estimates.

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

The registry record establishes that a completed phase 2, single-group study evaluated nivolumab for oral proliferative verrucous leukoplakia. It specifies a primary endpoint based on the percentage of participants whose best overall response was CR or PR, and it gives the response categories and follow-up description. It also records safety counts and lists several secondary outcomes. These details describe what was studied and how the primary outcome was defined.

The record information does not include the observed BORR percentage or its 95% confidence interval. Consequently, it does not show the primary response estimate or how precisely that estimate was measured. No conclusion about the amount of observed response can be drawn from the endpoint definition, enrollment, or safety counts. Numerical results for the listed secondary outcomes are also not reported in the registry record.

Even a reported response percentage from this design would describe outcomes in the nivolumab group, not a randomized comparison with another treatment. Since the study is single-group and has no masking, the design does not establish that any observed outcome was caused by nivolumab. Nor would a response rate by itself answer questions about response duration, quality of life, time to surgery, cancer-free survival, or overall survival. Those outcomes require their own results and interpretation.

The safety entries provide a descriptive account of participants affected by adverse events and the serious-event terms listed in the record. They do not establish comparative safety or causal attribution. The distinction between what the registry defines and what it numerically reports is important: the definitions and design are available, but the primary efficacy estimate and its uncertainty are not. The record therefore supports a description of the study's question and methods, while leaving the numerical efficacy interpretation unresolved.

14. Why This Trial Matters Statistically

This study illustrates why a clear endpoint definition is not a substitute for a reported endpoint result. The registry describes BORR as a percentage of participants achieving CR or PR and specifies a 95% confidence interval. Without the estimate and interval, readers cannot assess either the observed response level or the precision of the result. Reporting an estimate with its uncertainty is central to interpreting a binary clinical outcome.

The single-group design is also statistically important. It can describe observed response and safety in the enrolled participants, but it does not provide a randomized control contrast. Any observed outcome in such a design must be interpreted as an observation in the study group, rather than a causal estimate of how outcomes differ because of treatment. The registry's allocation and masking details make the absence of a like-for-like comparison explicit.

Finally, the record highlights the role of analysis transparency. The endpoint definition is detailed, but information about the analysis population, missing data, multiplicity, and a trial-specific sample-size justification is not reported in the registry record. Those elements help readers understand who contributed to an estimate, how uncertainty and incomplete observations were handled, and how multiple outcomes were interpreted. When those elements and the numerical primary result are unavailable, statistical assessment is necessarily limited to the design and definitions that are recorded.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The central limitation for interpreting efficacy is that the registry record does not report the observed BORR percentage or its 95% confidence interval. Although the primary outcome is defined in detail, the numerical result needed to assess response magnitude and precision is absent. The record information also does not include numerical results for the listed secondary outcomes.

The single-group design has no randomized comparator, and masking is listed as none. Outcomes therefore cannot be interpreted as a randomized treatment contrast. The registry does not report participant baseline characteristics or detailed eligibility criteria, limiting assessment of who the findings might describe. It also does not report the primary endpoint's analysis denominator or analysis population, or explain how missing or unevaluable responses were handled.

Assessment details are limited to the composite measurement-and-histology approach, response categories, reference for progressive disease, and the stated follow-up of up to 164 days. The registry record does not report further procedures for assessment timing, adjudication, or incomplete assessments. The record also does not report a multiplicity strategy, interim-analysis details, or a trial-specific sample-size justification. These omissions prevent a fuller appraisal of analytic choices and robustness.

For safety, the record gives affected-participant counts and serious-event terms, but the information does not provide event-level timing, duration, recurrence, or attribution to nivolumab. Without a comparator, the safety entries are descriptive rather than comparative. These limitations concern what can be inferred from the registry record; they do not establish that additional information does not exist elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Nivolumab in Treating Oral Proliferative Verrucous Leukoplakia — NCT03692325.
• Registry record last updated 2024-10-01; status last verified 2024-09.
• Results first posted 2024-04-22.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT03692325 is a completed phase 2, single-group study sponsored by Dana-Farber Cancer Institute. It evaluated nivolumab for oral proliferative verrucous leukoplakia, with enrollment recorded as 33. The study started on 2018-12-05 and had a primary completion date of 2022-09-01. Nivolumab was administered by IV infusion on Day 1 of each 28-day cycle, for a maximum of 4 cycles or until unacceptable toxicity or withdrawal of consent.

The primary endpoint was Best Overall Response Rate, defined as the percentage of participants achieving CR or PR, with a stated 95% confidence interval and follow-up up to 164 days. The observed response estimate and confidence interval are not reported in the registry record. The record lists serious adverse events in 6 participants, other adverse events in 33 participants, and 0 deaths. It describes no comparator arm, so efficacy and safety figures are not randomized comparisons.