REVEAL 1 (Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical HSIL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for REVEAL 1 (Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical HSIL) (NCT03185013), a randomized phase 3 study. The primary outcome is Percentage of Participants With No Evidence of Cervical HSIL on Histology and No Evidence of HPV-16 and/or HPV-18 in Cervical Samples.

2. Clinical Question

The clinical question therefore combines two types of outcome: a histologic assessment of cervical tissue and type-specific testing for HPV in cervical samples. A participant had to meet the stated response definition, rather than satisfy only one component of the combined endpoint. This makes the endpoint more specific than either histology or HPV testing considered alone, while also making its interpretation dependent on the registry’s particular handling of participants without an intervening tissue sample.

3. Trial Design

REVEAL 1 (NCT03185013) was a randomized, quadruple-masked, parallel-group Phase 3 study sponsored by Inovio Pharmaceuticals. The registry lists an enrollment of 201 and a completed study. The recorded start date is 2017-06-28, and primary completion is recorded as 2020-07-08. The registry describes the trial as prospective, randomized, double-blind, and placebo controlled; its masking field separately records quadruple masking.

Participants were assigned to VGX-3100 plus electroporation or placebo plus electroporation. In the active arm, the registry describes three intramuscular injections of 6 mg in 1 mL, followed by electroporation with the CELLECTRA™-5PSP device on Day 0, Week 4, and Week 12. The placebo arm received three 1 mL injections of matching placebo, also followed by electroporation on those scheduled occasions. Thus, electroporation was part of both arms, and the comparison concerns the addition of VGX-3100 within that treatment procedure rather than electroporation versus no electroporation.

The primary endpoint was assessed at Week 36. The primary analysis population was the intention-to-treat population, defined in the registry as all participants who were randomized. The posted arm denominators for this outcome are 138 for VGX-3100 plus electroporation and 63 for placebo plus electroporation. These denominators describe the posted outcome analysis; the registry record does not explain the difference between the enrollment figure and the arm denominators or give a detailed account of participant flow.

The registry lists cervical dysplasia and cervical HSIL among the conditions studied. The target group was adult women with histologically confirmed CIN2 or CIN3 associated with HPV-16 and/or HPV-18. Further details about the randomization procedure, allocation concealment, masking roles, and the original statistical design assumptions are 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.

Before assignment: A total of 201 participants with human papillomavirus (HPV)-16 and/or HPV-18 related high-grade squamous intraepithelial lesion (HSIL) of the cervix were randomized in this study, 138 in VGX-3100+EP and 63 in Placebo + EP.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population included all participants who were randomized.

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: ITT population included all participants who were randomized.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With No Evidence of Cervical HSIL on Histology and No Evidence of HPV-16 and/or HPV-18 in Cervical Samples, measured over Week 36.

The primary endpoint is the percentage of participants with no evidence of cervical HSIL on histology and no evidence of HPV-16 and/or HPV-18 in cervical samples at Week 36. The registry defines no evidence of HSIL as histology that is negative, shows squamous atypia, or shows LSIL. Cervical HPV samples were collected using ThinPrep®. A responder was required to satisfy the combined histology-and-HPV definition, subject to the registry’s rule that participants without an excision or biopsy sample between the initial dose and Week 36 were also counted as responders.

A combined endpoint can represent more than one aspect of a disease-related outcome: tissue findings and detection of the specified HPV types. It is used to classify response using both components rather than treating a histologic result or an HPV result by itself as sufficient. General statistical point: combining components can make the endpoint harder to interpret as a single construct, because a group difference may reflect one component, the other, or both. Component outcomes are therefore useful context, but they do not replace the prespecified primary endpoint.

The percentage is a binary outcome: each participant is classified as a responder or not a responder under the stated definition. The primary population includes all randomized participants. The way participants without a biopsy or excision sample were classified is consequential to the endpoint’s meaning; further detail on missing-data handling beyond that rule is not reported in the registry record.

7. Results Posted in the Registry

• VGX-3100 + Electroporation (EP): 22.5% (31/138) versus 11.1% (7/63) on control; risk difference 11.4 percentage points (95% CI 0.9 to 21.8), risk ratio 2.02 (0.94–4.34); unadjusted two-proportion z-test p = 0.057.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants With No Evidence of Cervical HSIL on Histology

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VGX-3100 + Electroporation (EP): 31.9% (44/138) versus 19.0% (12/63) on control; risk difference 12.8 percentage points (95% CI 0.4 to 25.3), risk ratio 1.67 (0.95–2.94); unadjusted two-proportion z-test p = 0.060.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between VGX-3100 + Electroporation (EP) and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With No Evidence of HPV-16 and/or HPV-18 in Cervical Samples by Type Specific HPV Testing

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VGX-3100 + Electroporation (EP): 34.1% (47/138) versus 15.9% (10/63) on control; risk difference 18.2 percentage points (95% CI 6.2 to 30.2), risk ratio 2.15 (1.16–3.96); unadjusted two-proportion z-test p = 0.008.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for VGX-3100 + Electroporation (EP) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Participants With No Evidence of LSIL or HSIL on Histology

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • VGX-3100 + Electroporation (EP): 24.6% (34/138) versus 11.1% (7/63) on control; risk difference 13.5 percentage points (95% CI 2.9 to 24.1), risk ratio 2.22 (1.04–4.73); unadjusted two-proportion z-test p = 0.027.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for VGX-3100 + Electroporation (EP) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes cover histology, cervical HPV testing, combinations of histologic and virologic findings, disease progression, HPV findings at non-cervical locations, antibody concentrations, and adverse events. The subset of posted Week 36 binary outcomes generally has higher response percentages in the VGX-3100 plus electroporation arm than in the placebo plus electroporation arm. This overall direction is broadly consistent with the positive point estimate for the primary combined endpoint. It does not remove the uncertainty in the primary analysis or establish that every endpoint measures the same aspect of response.

Secondary measures can help describe whether the primary pattern is accompanied by changes in its component outcomes. They are not interchangeable with the primary endpoint: histology alone, HPV testing alone, and a combined response definition classify participants differently. For that reason, the secondary results provide context rather than a replacement test of the primary question.

There are multiple secondary outcomes and analyses. If each is interpreted as a separate confirmatory test without adjustment, the overall chance of at least one apparently notable result may increase. General statistical point: multiplicity procedures or a prespecified hierarchy can help control that risk. The registry record does not report a multiplicity adjustment, testing hierarchy, or a complete statistical plan for the secondary analyses. Their unadjusted results should consequently carry less weight than a clearly prespecified primary analysis and should be interpreted as supportive rather than definitive evidence.

The registry lists 10 posted secondary outcomes, while the listed outcome set includes measures of different types and time frames. The posted binary outcomes at Week 36 are a subset of that broader set. A consistent direction across related measures can be informative, but it does not prove that the findings are independent: some outcomes may be conceptually or statistically related. The record does not report a joint analysis of these outcomes.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Following Investigational Treatment for the Duration of the Study
• Percentage of Participants With No Evidence of Cervical HSIL on Histology
• Percentage of Participants With No Evidence of HPV-16 and/or HPV-18 in Cervical Samples by Type Specific HPV Testing
• Percentage of Participants With No Evidence of LSIL or HSIL on Histology
• Percentage of Participants With No Evidence of LSIL or HSIL and No Evidence of HPV-16 and/or HPV-18
• Percentage of Participants With No Progression of Cervical HSIL to Cervical Carcinoma
• Percentage of Participants Who Have Cleared HPV-16 and/or HPV-18 in Non-cervical Anatomic Locations
• Levels of Serum Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations

9. Statistical Interpretation

10. Statistical Methods Explained

What does a percentage endpoint mean?

The primary outcome is binary at the participant level: a participant either meets the responder definition or does not. The arm percentages describe the proportion classified as responders under that definition. They do not measure the degree of histologic change or the amount of HPV detected. The numerator and denominator approach is suitable for an outcome recorded as a category, but the resulting percentage depends on how the endpoint and any missing observations are defined.

The analysis population is stated as intention-to-treat, including all randomized participants. This principle preserves the randomized group comparison by analyzing participants according to assigned group. The registry record does not give further detail on whether every randomized participant contributed a directly observed Week 36 result, nor does it describe additional methods for handling unavailable outcome data. The special responder rule for participants without a biopsy or excision sample is reported and is part of the primary endpoint definition.

What does a risk difference describe?

A difference in percentage compares the response proportions in the two randomized groups by subtraction, expressed in percentage points. A value above zero for the active-versus-placebo contrast corresponds to a higher observed response percentage in the active arm. Unlike a relative measure, a percentage-point difference describes the absolute separation between the group proportions. General statistical point: absolute measures are often easier to relate to the observed event frequency, while relative measures answer a different question about proportional change. Neither measure, by itself, resolves uncertainty or establishes a causal mechanism.

The posted primary analysis is labelled as a Miettinen and Nurminen method analysis of the difference in percentage. The sponsor reports a difference of 11.4 percentage points, a 95% confidence interval from -0.4 to 21.2, and p = 0.029. The registry also lists an unadjusted re-calculation based on posted summary statistics, with p = 0.057. These analyses do not agree fully. The sponsor’s own analysis takes precedence, but the record does not explain why the two approaches differ or provide enough procedural detail to reproduce the sponsor’s result.

How should a confidence interval be read?

A confidence interval gives a range of values compatible with the data and the analysis procedure, subject to the assumptions used to calculate it. It is not a guarantee that the true value lies in that particular interval, nor does it give the probability that a specific effect is true. For the primary sponsor analysis, the interval extends from -0.4 to 21.2 percentage points. Because the interval includes zero, it includes a value representing no difference between the groups. The p-value and interval are both relevant summaries, but they are not interchangeable: the interval communicates a range of estimates, while a p-value measures compatibility with a specified null model under an analysis procedure.

General statistical point: a confidence interval can be wide when the data are not precise enough to distinguish among a broad range of effects. Its width depends on factors such as sample size, event frequency, and the interval method. Those general factors do not establish the cause of the width in this trial; the posted denominators and response percentages are the available context.

Why compare the sponsor result with a re-calculation?

A simple unadjusted re-calculation is a useful arithmetic check on whether posted group summaries yield a broadly similar estimate under a basic approach. It is not necessarily the same as the trial’s planned or sponsor-reported analysis. The registry labels the sponsor method for the primary analysis, while it does not report all details needed to recreate that analysis. The discrepancy between the sponsor analysis and re-calculation therefore matters: it cautions against treating the simpler calculation as the definitive trial result. For this record, the sponsor’s reported analysis is the primary reference.

The re-calculated p-value should not be treated as a second independent trial result. It comes from the same posted group information, not new participant data. It also does not resolve which analysis was prespecified, since the original analysis plan is not reported in the registry record. The registry record does not report whether alternative models, covariate adjustments, or interim analyses were used.

What does statistical significance not tell us?

A p-value is not the probability that the null hypothesis is true, nor is it a measure of effect size. A threshold-based interpretation can also hide the range of possible effects reflected by the confidence interval. General statistical point: statistical evidence and clinical importance are distinct questions. The registry record does not provide a clinical threshold for a meaningful difference, so the posted statistical summaries alone cannot determine whether a particular estimated difference would be clinically important.

For secondary outcomes, unadjusted p-values and intervals require additional caution because several outcomes are examined. When many statistical comparisons are made, the chance of seeing apparently notable results by chance can rise. A multiplicity adjustment or an explicit testing hierarchy can address this concern, but the registry record does not report a multiplicity procedure. Accordingly, secondary results are best treated as supportive or exploratory rather than as equivalent to a single primary test.

11. Confidence Intervals and Precision

The sponsor-reported primary estimate is a difference of 11.4 percentage points, with a 95% confidence interval from -0.4 to 21.2. The interval extends across zero, so the posted estimate is compatible with no group difference as well as with positive differences of varying size. Its breadth means the point estimate should not be read as a precise estimate of the true difference. The reported p-value is 0.029; the unadjusted re-calculation gives p = 0.057, reinforcing that the discrepancy between analyses affects the interpretation of the statistical evidence.

Confidence intervals describe uncertainty under the analysis method and its assumptions. They do not indicate the range of individual participant outcomes, and they do not assign a probability to the true effect. A 95% confidence level is a property of the interval procedure under repeated use, not a claim that there is a 95% probability that this one interval contains the true effect.

The posted primary denominators are 138 and 63. The arm sizes are unequal, and the number of responders is limited relative to the number analyzed. General statistical point: binary outcomes with limited event counts can yield uncertain estimates, and precision usually improves with more information. The registry record does not provide a precision target or the original sample-size justification, so the observed interval should be considered on its own terms.

Precision is separate from whether a test crosses a conventional significance threshold. The sponsor estimate’s interval spans the null, while the p-value is reported as 0.029; these summaries should not be collapsed into a single yes-or-no conclusion. The simple re-calculation’s different p-value is another reason to give priority to the sponsor analysis while acknowledging uncertainty and the unexplained discrepancy.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations are based on the observed primary effect and are planning examples, not the trial’s original design calculation. For this binary endpoint, the figures are participants per arm, not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

For planning at 100% of the observed effect, the illustration gives 169 participants per arm for 80% power and 226 participants per arm for 90% power. At 75% of the observed effect, it gives 281 participants per arm for 80% power and 375 participants per arm for 90% power. At 50% of the observed effect, it gives 584 participants per arm for 80% power and 781 participants per arm for 90% power.

In plain language, 80% power means that, if the assumed effect and planning assumptions were correct, a study of the indicated size would have an 80% chance of detecting an effect at the stated significance level under the specified test. The 90% column expresses the corresponding planning target at a higher probability of detection. These are prospective planning concepts, not probabilities that this trial’s result is correct. The figures are not observed power.

Smaller effects are harder to distinguish from random variation, so planning for a smaller fraction of the observed effect requires more participants per arm. These illustrations rely on the effect observed in this trial, which may not be the effect a future study would encounter. They should therefore be read as conditional examples rather than as a recommended sample size or evidence that a particular study would achieve its target.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.111; treatment proportion p₁ = 0.225; average p̄ = 0.168.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5286 = 1.0360.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5224 = 0.4397.
4. n = (1.0360 + 0.4397)² / (0.1135)² = 169.0, rounded up to 169 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.111111111111111                          # control proportion
p1 <- 0.22463768115942                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3185013)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 169 (80% power), 226 (90% power)
 75% of observed effect: n per arm = 281 (80% power), 375 (90% power)
 50% of observed effect: n per arm = 584 (80% power), 781 (90% power)
power.prop.test: 169 
Simulated power at n = 169 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor’s primary analysis reports a difference in percentage of 11.4, with a 95% confidence interval from -0.4 to 21.2 and p = 0.029. The posted summary statistics also support an unadjusted re-calculation, which gives p = 0.057. The record marks a discrepancy between these results but does not explain its source. Differences can arise when an analysis method or underlying analysis set differs from a simple calculation using posted summaries; the available record does not establish which explanation applies.

Because the sponsor’s own analysis is the trial’s reported analysis, it takes precedence over the simple re-calculation. The re-calculation is a check, not a substitute for the sponsor result and not an independent replication. The sponsor interval includes zero, even though the sponsor-reported p-value is 0.029. The re-calculated p-value differs, so the statistical evidence is sensitive to the analysis used. Both features warrant transparent reporting rather than selection of only the more favorable statistic.

The registry record identifies the primary method as Miettinen and Nurminen but does not provide enough detail to reproduce the analysis or explain the discrepancy. The original statistical analysis plan, any adjustments, and the handling of all observations are not reported in the registry record. Readers should therefore use the sponsor’s reported estimate and interval as the principal trial result while recognizing that the posted summaries do not permit a full independent audit.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies an intention-to-treat primary population consisting of all randomized participants. This makes the randomized groups the basis for the primary comparison. The record does not provide a detailed participant-flow account, a full analysis-population description for each outcome, or an explanation of how every unavailable observation was handled. The endpoint definition does specify that participants without an excision or biopsy sample between the initial dose and Week 36 were considered responders. That rule is part of the outcome definition, not a complete account of all possible missing-data scenarios.

Further details about missing HPV samples, missing histology results, withdrawals, or sensitivity analyses are not reported in the registry record. Without those details, it is difficult to assess how robust the primary result is to alternative assumptions about participants whose outcome status could not otherwise be determined. The record also does not report whether missingness differed by randomized group.

The registry posts numerous secondary outcomes and analyses. Multiplicity matters because repeated testing can increase the chance of a nominally notable result even when there is no underlying effect. An adjustment, hierarchy, or prespecified distinction between confirmatory and exploratory tests could clarify how secondary p-values should be interpreted. Such a procedure is not reported in the registry record. The secondary findings should therefore not be treated as though each had the same evidential standing as the primary question.

The original statistical analysis plan, including the planned handling of missing data, any interim analyses, covariate adjustment, and multiplicity strategy, is not reported in the registry record. These omissions limit independent assessment of whether the posted analyses follow the original plan. They do not show that a particular method was or was not used; they mean the relevant details are unavailable in the registry record.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: squamous cell carcinoma of the cervix (3.7%), cervix carcinoma (3.2%), adenosquamous carcinoma of the cervix (1.6%), upper limb fracture (1.6%), abortion spontaneous (1.6%).

For serious adverse events, the registry lists 13 affected participants among 136 at risk in the VGX-3100 plus electroporation group and 6 among 62 at risk in the placebo plus electroporation group. For other adverse events, the posted figures are 131 among 136 and 61 among 62, respectively. The death counts are 1 in the VGX-3100 group and 0 in the placebo group. These counts describe the posted safety summaries and their stated denominators; they are not adjusted comparisons between treatment groups.

The listed serious-event terms include Squamous Cell Carcinoma of the Cervix at 3.7%, Cervix Carcinoma at 3.2%, Adenosquamous Carcinoma of the Cervix at 1.6%, Upper Limb Fracture at 1.6%, Abortion Spontaneous at 1.6%, and Ectopic Pregnancy at 1.6%. The registry record does not establish from these figures whether an event was caused by treatment. Event terms and participant counts should not be interpreted as causal evidence or as a complete characterization of risk.

The posted safety summaries do not include a statistical comparison, detailed timing, exposure-adjusted rates, or a complete narrative for each event. The registry record does not report those details. The figures therefore support a descriptive account of reported events, not a conclusion about comparative safety.

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

The primary endpoint estimates how often participants met a particular combined response definition at Week 36. In the posted results, the response percentage was higher in the VGX-3100 plus electroporation arm than in the placebo plus electroporation arm. The sponsor’s reported difference is positive, but its confidence interval ranges from -0.4 to 21.2 percentage points and includes zero. The reported p-value is 0.029, while an unadjusted re-calculation gives p = 0.057. The discrepancy means the reported statistical evidence should be interpreted with care, giving precedence to the sponsor’s own analysis while acknowledging the unresolved difference.

The endpoint does not directly describe every aspect of cervical disease or HPV status. It combines tissue histology and cervical HPV testing, and it includes a special responder classification for participants without an intervening excision or biopsy sample. Its result therefore applies to that operational definition and time point. It does not by itself establish how long a response lasts or what happens beyond the outcomes and time frames posted in the registry.

The trial’s comparison is VGX-3100 plus electroporation versus placebo plus electroporation. It does not isolate the effect of electroporation compared with no electroporation. The result also does not answer questions about populations outside the described adult women with HPV-16 and/or HPV-18 related HSIL, or about outcomes not reported in the registry record.

Statistical results do not determine an individual outcome. A group percentage is not a prediction for a particular participant, and a confidence interval is not a range of individual responses. The registry record does not report a threshold for clinical importance, so the numerical difference cannot by itself establish the practical importance of the result. The safety summaries are descriptive and do not establish whether reported events were caused by treatment. No treatment recommendation follows from these statistical summaries alone.

18. Why This Trial Matters Statistically

This trial illustrates why the headline estimate, confidence interval, and p-value should be read together. The sponsor-reported primary estimate is positive, but its confidence interval includes zero, and a simple unadjusted re-calculation gives a different p-value. A reader who focuses only on the point estimate or only on a threshold-crossing p-value would miss important information about uncertainty and analytic sensitivity. The unexplained discrepancy makes transparent reporting of the analysis method especially important.

The endpoint also shows how operational definitions shape trial results. It combines histologic and HPV findings and treats participants without a biopsy or excision sample during the specified interval as responders. That rule is part of the estimand readers are interpreting. Knowing the endpoint definition is essential to understanding what the response percentage represents and what it does not represent.

Finally, this is a multi-outcome trial. Secondary results can add useful context, particularly when they address components related to the primary endpoint, but unadjusted analyses across multiple outcomes have less confirmatory force. The registry record’s missing details about multiplicity, missing-data methods, and the original statistical plan illustrate why a public result summary may not contain all information needed for a full statistical audit. These are general lessons in reading clinical trial evidence, not conclusions about the biological mechanism or the clinical use of the intervention.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record leaves several trial-specific uncertainties. It does not explain the difference between total enrollment of 201 and the posted primary outcome denominators of 138 and 63, or provide a complete participant-flow account. The primary analysis population is identified as all randomized participants, but details about missing observations, withdrawals, and sensitivity analyses are not reported. The responder rule for participants without an excision or biopsy sample is stated, yet the record does not describe how other unavailable histology or HPV observations were treated.

The sponsor’s reported primary analysis and the unadjusted re-calculation differ, and the record does not explain why. Although the sponsor’s result takes precedence, the details needed to reproduce it are not reported. The original sample-size justification, planned analysis assumptions, interim analyses, and multiplicity approach are also not reported in the registry record. These gaps limit an independent assessment of the analysis plan and the confirmatory status of secondary findings.

The endpoint is measured at Week 36 and combines histology with cervical HPV testing. The posted result does not, by itself, describe durability or outcomes beyond the reported time frame. The comparison includes electroporation in both arms, so it cannot estimate the effect of electroporation alone. Safety data are presented descriptively; the record does not report a formal comparative safety analysis or establish causality for serious adverse events. These limits define what can be inferred from the posted record and should not be filled by assumptions.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: REVEAL 1 (Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical HSIL) — NCT03185013.
• Registry record last updated 2023-07-27; status last verified 2023-07.
• Results first posted 2023-07-25.
• 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.

23. Record Summary

REVEAL 1 (NCT03185013) was a completed randomized, quadruple-masked, parallel-group Phase 3 trial sponsored by Inovio Pharmaceuticals. It enrolled 201 participants and compared VGX-3100 plus electroporation with matching placebo plus electroporation in adult women with HPV-16 and/or HPV-18 related cervical HSIL.

The primary endpoint was the Week 36 percentage meeting a combined histology-and-HPV response definition. The posted response percentages were 22.5% and 11.1%. The sponsor reported a difference of 11.4 percentage points, a 95% confidence interval from -0.4 to 21.2, and p = 0.029. An unadjusted re-calculation gives p = 0.057; the sponsor analysis takes precedence, and the reason for the discrepancy is not reported in the registry record.

The record also posts secondary efficacy and safety outcomes. Details on the original sample-size justification, missing-data methods, multiplicity, and full analysis plan are not reported in the registry record, limiting independent assessment of the analyses.