Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV+ Lymphoid Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV+ Lymphoid Malignancies (NCT03397706), a non-randomized phase 1, phase 2 study. The primary outcome is Number (Proportion) of Participants With Adverse Events (AEs).

2. Clinical Question

In statistical terms, the registry record chiefly supports a descriptive safety question: what adverse events were recorded among treated participants in this study? The study’s stated purpose also included defining a recommended Phase 2 dose and evaluating the combination in relapsed or refractory disease. The record lists secondary outcomes such as response duration, time to response, progression-free survival, disease control rate, overall survival, and pharmacokinetic measures. Their presence as outcomes does not establish that results for them are reported.

3. Trial Design

NCT03397706 was a Phase 1b/2, open-label, non-randomized study with a sequential model. It began on 2018-03-29, had a primary completion date of 2023-04-01, and is recorded as completed. The registry lists enrollment as 64. That figure describes enrollment in the study record; it should not be substituted for the denominator of a particular outcome, which may use a defined analysis population.

The Phase 1b part used dose escalation. The arm descriptions identify five dose-escalation cohorts receiving VRx-3996 with valganciclovir. Safety group labels in the posted results include Phase 1b Dose Escalation Cohort 1, Cohort 2a, Cohort 2b, Cohort 2c, and Cohort 3. The Phase 2 part expanded at the recommended Phase 2 dose and had capsule and tablet groups. The registry summary says Phase 1b was designed to define a recommended Phase 2 dose, with the combination’s efficacy to be evaluated in relapsed or refractory Epstein-Barr virus-associated lymphoma.

Because the study was not randomized and had no masking, comparisons across cohorts or expansion groups are descriptive rather than controlled treatment comparisons. Changes in outcomes across groups cannot be attributed to dose or formulation alone on the basis of this design. The registry record does not report the dose levels, the detailed assignment process, or a statistical plan for comparing groups. It also does not report a sample-size justification. The posted sample-size planning illustration is separate from the trial’s own design assumptions and is not an observed-power result.

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: Starting valganciclovir dosage reductions based on creatinine clearance were allowed for participants with renal impairment.

Only the first 6 of 7 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set, defined as all enrolled patients who received at least 1 dose of study treatment. Valganciclovir dosage reductions were allowed for participants with renal impairment at study entry or during study treatment.

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: Starting valganciclovir dosage reductions based on creatinine clearance were allowed for participants with renal impairment.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number (Proportion) of Participants With Adverse Events (AEs), measured over Up to approximately 2 years.

The primary endpoint is the number and proportion of participants with at least one adverse event that emerged after treatment began, or an existing event that worsened after the first dose. The timeframe is up to approximately 2 years. The registry defines the Safety Analysis Set as all enrolled patients who received at least 1 dose of study treatment. Valganciclovir dose reductions were allowed for participants with renal impairment at study entry or during treatment.

A participant-level endpoint counts whether a person experienced an event, rather than counting every event episode. That makes it a way to describe how widely adverse events occurred in the defined safety population. It does not, by itself, describe event severity, duration, recurrence, or whether an event was caused by a study drug. Those questions require additional definitions and results.

Adverse-event monitoring is a relevant primary outcome in a dose-escalation and expansion study because the record’s stated Phase 1b purpose included defining a recommended Phase 2 dose. The posted safety results separately identify serious adverse events and other adverse events by group. Those summaries should not be conflated with the primary endpoint unless their definitions and denominators match it. The registry record does not provide a comparative primary efficacy endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s primary outcome is a binary participant-level measure: whether a participant experienced at least one qualifying adverse event during the stated timeframe. For a binary outcome, the basic descriptive quantities are a count of participants with the event and a proportion calculated against a defined denominator. The posted record describes the endpoint as a number and proportion, and defines the safety population as enrolled patients who received at least 1 dose. The specific primary-outcome result is not reported in the registry record among the registry entries; group-level adverse-event counts are reported separately.

What does a count or proportion tell the reader?

A count tells how many participants met the endpoint definition. A proportion relates that count to the eligible population and can make groups of different sizes easier to understand. Neither quantity alone conveys how uncertain the estimate is. A confidence interval, when reported, expresses a range of values compatible with the data and the interval’s stated method. The registry record does not report confidence intervals for the primary endpoint in the registry record. Without them, the precision of the primary estimate cannot be assessed from a confidence interval.

The endpoint definition matters. The primary outcome counts a participant if an adverse event started after the first dose or if a pre-existing event worsened after the first dose. It is therefore not simply a count of all medical events during the study. It is also distinct from an event-level tally: a person can have multiple events but is counted once for a participant-level “at least one” outcome. The registry’s serious-event summaries and other-event summaries supply additional descriptions, but do not replace the primary endpoint definition.

Why does the study design affect interpretation?

Random assignment can help balance measured and unmeasured characteristics between comparison groups. This study was non-randomized, open-label, and sequential, so its cohorts are not randomized controls. In a dose-escalation setting, the groups may also reflect different stages or dosing decisions. The Phase 2 capsule and tablet groups were both described as receiving the recommended Phase 2 dose, but the registry record does not establish that those groups were directly comparable. Group differences are consequently descriptive and cannot isolate a causal effect of dose or formulation.

Open-label means masking was absent. Knowledge of treatment can influence reporting, assessment, and decisions about care or follow-up. That general possibility is relevant when interpreting adverse-event reporting, although the registry record does not quantify whether it affected these results. The record also does not report a blinded event-adjudication process, adjustment for participant characteristics, or a method for comparing the groups. Those features should not be assumed.

How should uncertainty and planning be distinguished?

Statistical uncertainty is different from clinical importance and from a simple difference in observed counts. General statistical principle: an estimate based on fewer observations tends to be less precise than an otherwise comparable estimate based on more observations. This does not justify assigning a particular uncertainty range to these groups without the relevant calculation and assumptions. No such interval is reported in the registry record.

The posted sample-size planning illustration is based on the observed effect and states assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes planning to detect a stated fraction of the observed effect. It is not the trial’s own design justification, and it is not observed power. The registry record does not report the numerical planning outputs in the registry record, so they cannot be used to characterize the trial’s precision or adequacy. General principle: planning calculations depend on the assumed effect, variability or event rate, allocation, and chosen error threshold. A planning illustration does not change what the study actually observed.

What can be inferred from the listed terms?

The serious-event term percentages identify terms that the registry lists among the most frequent, but the denominator and calculation basis are not reported. They may not be interpreted as a percentage of all participants, all serious events, or all events unless the record states that basis. The event terms also do not establish causation. General principle: a reported adverse event is an event observed during a study; attribution to treatment requires an explicit assessment and should not be inferred from occurrence alone.

For these reasons, the most defensible statistical reading is descriptive: use the stated group denominators and affected counts, retain the distinction between serious and other adverse events, and avoid causal or controlled-comparison claims. The registry record does not report a primary efficacy analysis, a confidence interval, or the methods needed to reconstruct one.

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("Phase 1b Dose Escalation Cohort 1", "Phase 1b Dose Escalation Cohort 2a", "Phase 1b Dose Escalation Cohort 2b", "Phase 1b Dose Escalation Cohort 2c", "Phase 1b Dose Escalation Cohort 3", "Phase 2 Dose Expansion - Capsule")
n      <- c(7, 5, 4, 4, 5, 30)
events <- c(7, 5, 4, 4, 5, 30)
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  Phase 1b Dose Escalation Cohort 1  7  7  100.0  59.0  100.0  64.6  100.0  63.1  99.7
ARM  Phase 1b Dose Escalation Cohort 2a  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Phase 1b Dose Escalation Cohort 2b  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Phase 1b Dose Escalation Cohort 2c  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Phase 1b Dose Escalation Cohort 3  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Phase 2 Dose Expansion - Capsule  30  30  100.0  88.4  100.0  88.6  100.0  88.8  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and names secondary outcomes covering response, disease control, survival, and pharmacokinetic measures. It reports 0 analyses in the record represented by these registry entries. The outcomes’ inclusion in the registry does not mean that each was analyzed or that results are available. No multiplicity adjustment, testing hierarchy, or strategy for controlling false-positive findings is reported in the registry record. General principle: when many outcomes are tested, the chance of at least one apparently notable result can increase, so prespecified priorities and adjustment methods can matter. No such method should be presumed.

The primary outcome population is defined as enrolled patients who received at least 1 dose of study treatment. The registry record does not report how missing adverse-event information was handled, whether all participants had complete follow-up, or whether participants were excluded from particular summaries. The outcome timeframe is up to approximately 2 years, but the record does not state how variable observation time or early discontinuation was handled in the primary analysis.

The efficacy analysis population, analysis methods for the secondary outcomes, and any missing-data assumptions are not reported in the registry record. Nor are statistical comparisons, confidence intervals, or an analysis plan available in the registry record. These omissions limit assessment of how robust results would be to incomplete observation or multiple outcome testing. The group-level safety counts remain useful as descriptive records, but they cannot answer questions that require unreported denominators, follow-up detail, or inferential methods.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: tumour necrosis (25.0%), acute kidney injury (25.0%), enterocolitis viral (25.0%), pharyngitis (25.0%), dyspnoea (20.0%).

The serious adverse-event counts are reported by study group: Cohort 1 had 2 affected participants among 7 at risk; Cohort 2a had 2 among 5; Cohort 2b had 2 among 4; Cohort 2c had 1 among 4; Cohort 3 had 1 among 5; the capsule expansion group had 11 among 30; and the tablet expansion group had 4 among 9. These are group-specific counts, not randomized comparisons. The study’s non-randomized design does not support treating differences between these figures as treatment effects.

The listed counts for other adverse events match the at-risk count in each group. The record also lists deaths by group, but the relationship of those deaths to treatment, their timing, and their causes are not reported in the registry record. The serious-event term percentages are tumour necrosis, acute kidney injury, enterocolitis viral, and pharyngitis at 25.0% each, and dyspnoea and pyrexia at 20.0% each. The denominator behind these term percentages is not reported.

Seriousness is not the same as treatment causality, and an event appearing in a study record does not establish that a study drug caused it. These summaries also do not convey event duration, recurrence, or participant-level overlap among event terms. Read them as descriptive safety reporting within the listed groups, not as estimates from a controlled comparison.

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

The registry record documents a completed, open-label, non-randomized Phase 1b/2 study of VRx-3996 with valganciclovir in Epstein-Barr virus-associated lymphoid malignancies. Its stated aims included defining a recommended Phase 2 dose and evaluating the combination in relapsed or refractory Epstein-Barr virus-associated lymphoma. It reports group-level safety counts and selected serious-event terms. Those observations describe what was recorded in this study population.

The safety counts do not establish whether the combination caused any particular event. They do not compare the regimen with a randomized control, and the cohorts should not be treated as equivalent groups. The listed deaths likewise cannot be attributed to treatment from the information reported. The serious-event term percentages have no stated denominator in the registry record, so they cannot be read as participant risks.

The record’s primary outcome is the number and proportion of participants with at least one treatment-emergent adverse event, but the primary result is not reported in the registry record. Although the registry lists response, progression-free survival, overall survival, and other secondary outcomes, results for them are not reported in the registry record. The record also reports 0 analyses. Consequently, the registry entries do not support a conclusion about efficacy, comparative safety, or the size and precision of an effect.

General statistical principle: evidence from a non-randomized study can describe outcomes in the participants observed, while causal claims require stronger assumptions and suitable comparisons. The design, population definitions, missing-data handling, and analysis plan all shape what can be inferred. In this record, several of those details are not reported. The appropriate interpretation is therefore bounded: the data provide descriptive safety information by group, but do not establish a controlled treatment effect or answer the listed efficacy questions.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining dose escalation with a Phase 2 expansion in a non-randomized, open-label design. The Phase 1b purpose was to define a recommended Phase 2 dose, while the registry summary describes an intended efficacy evaluation in relapsed or refractory Epstein-Barr virus-associated lymphoma. Those aims make safety description and clear population definitions important, but they do not turn cohort observations into randomized evidence.

The registry’s safety summaries show why denominators must accompany event counts. The affected and at-risk counts differ by group, and the primary Safety Analysis Set has a specific definition based on treatment receipt. The enrollment figure of 64 is not automatically the denominator for every outcome. Careful reading preserves the distinction between enrollment, the safety population, and group-specific at-risk counts without combining them into a new total.

The record also illustrates the difference between registering outcomes and reporting analyses. It lists 14 outcome measures, including response, survival, and pharmacokinetic outcomes, while reporting 0 analyses in the registry record. Outcome names alone do not provide estimates or uncertainty. Without reported efficacy results, confidence intervals, or analysis methods, readers cannot assess the magnitude or precision of an efficacy finding from this record.

Finally, the safety term percentages are presented without a reported denominator, and the group design does not support direct causal comparisons. These features make transparent reporting of denominators, event attribution, follow-up, missing data, and analysis methods especially important. The available registry information supports a bounded descriptive interpretation rather than a comparative conclusion.

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 design limits causal interpretation. Allocation was non-randomized, masking was absent, and the study followed a sequential model. The dose-escalation cohorts and capsule and tablet expansion groups are not randomized control arms. Differences among their event counts may reflect differences in participants, exposure, follow-up, dose, or other factors, and the registry record does not report adjustment for these factors.

The primary safety outcome is defined for a Safety Analysis Set, but the primary result itself is not reported in the registry record. The study enrollment figure should not be treated as the endpoint denominator. Group-specific safety counts are available, yet the registry record does not give the detailed analysis methods, uncertainty intervals, or complete context for the deaths listed. It also does not report the denominator used for the serious-event term percentages.

The outcome timeframe is up to approximately 2 years, but information on participant-level follow-up, discontinuation, missing observations, and handling of incomplete follow-up is not reported in the registry record. The record lists 14 outcome measures and 0 analyses; no multiplicity strategy, efficacy analysis population, or statistical plan is reported in the registry record. Thus, the listed secondary outcome names cannot be treated as reported efficacy findings.

Finally, the planning illustration uses stated assumptions and is not described as the trial’s design justification. Its sample-size results are not included in the registry record, and it is not observed power. These limitations mean the posted information is most informative as a record of study design and descriptive safety reporting, not as a basis for estimating a controlled treatment effect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose Escalation & Expansion Study of Oral VRx-3996 & Valganciclovir in Subjects With EBV+ Lymphoid Malignancies — NCT03397706.
• Registry record last updated 2025-03-20; status last verified 2025-03.
• Results first posted 2025-03-20.
• 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

NCT03397706 is a completed Phase 1b/2, open-label, non-randomized, sequential study of VRx-3996 with valganciclovir for Epstein-Barr virus-associated lymphoid malignancies. Enrollment is listed as 64. The study included Phase 1b dose escalation and Phase 2 capsule and tablet expansion at the recommended Phase 2 dose. Its stated aims included dose definition and evaluation of the combination in relapsed or refractory disease.

The primary outcome is the number and proportion of participants with at least one treatment-emergent adverse event, in a safety population of enrolled patients who received at least 1 dose, over up to approximately 2 years. Group-level serious and other adverse-event counts are reported. The record lists 14 outcome measures and 0 analyses; efficacy results, inferential methods, missing-data handling, and multiplicity procedures are not reported in the registry record.