Efficacy of Oral Famciclovir 125mg Comparing to Aciclovir 200 mg Treatment in Patients With Active Recurrent Genital Herpes: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of Oral Famciclovir 125mg Comparing to Aciclovir 200 mg Treatment in Patients With Active Recurrent Genital Herpes (NCT01281007), a randomized phase 3 study. The primary outcome is Efficacy Will be Evaluated by the Proportion of Subjects With Non Herpes Manifestation.

2. Clinical Question

3. Trial Design

The registry describes a Phase 3, randomized, multicenter, parallel-group study comparing famciclovir 125 mg with aciclovir 200 mg in patients with active recurrent genital herpes. The study is marked completed. Its reported enrollment is 150. The posted arm results each list 75 participants, with the same denominator reported for the safety outcomes.

The record marks masking as none. Thus, the posted design is open-label rather than masked. Allocation is recorded as randomized, but the randomization procedure, allocation concealment, and any safeguards against selection bias are not reported in the registry record. The record also does not specify whether outcome assessment was conducted by assessors unaware of group assignment.

The famciclovir regimen was 1 tablet every 12 hours for 5 days. The aciclovir regimen was 1 tablet every 4 hours, excluding the nocturnal dose, for 5 days. The primary endpoint was evaluated at Day 5. A secondary outcome concerned the occurrence of adverse events. The registry lists one posted secondary outcome and two outcome measures, but the record does not give detailed definitions or assessment procedures for the safety outcome.

The listed study start is 2012-07, and primary completion is listed as 2015-01. Details about recruitment, follow-up beyond the endpoint timeframe, protocol deviations, and the conduct of the study are not reported in the registry record. Its statistical analysis plan, including any prespecified adjusted model, is also not reported. The randomized comparison can therefore be described from the posted design and results, while important details needed to assess implementation and analysis remain unavailable in the 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

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 Efficacy Will be Evaluated by the Proportion of Subjects With Non Herpes Manifestation, measured over Day 5.

The primary endpoint is titled as the efficacy assessment by the proportion of subjects with a non-herpes manifestation. It is measured at Day 5 and reported as a number of subjects. The listed symptoms evaluated are erythema, papule, vesicle, ulcer, crust, or healed skin. The registry record does not further explain how the phrase “non-herpes manifestation” relates to this symptom list, how a subject was classified, or how missing Day 5 assessments were handled.

A binary endpoint records whether each participant meets a defined condition or does not. In general, this format allows a comparison of the frequency of an event between randomized groups. Here, the posted group counts are 73 of 75 for famciclovir and 52 of 75 for aciclovir. These counts describe the recorded endpoint; they do not, by themselves, explain the clinical meaning of the classification or establish why the groups differed.

The endpoint is useful for a between-group comparison because both arms have a reported count and denominator at the same stated time point. Interpretation depends on the endpoint being defined and assessed consistently across groups. The registry record does not report enough operational detail to assess that consistency independently. The result should therefore be read as a comparison of the endpoint as registered and posted, rather than as a broader measure of all symptoms, disease course, or patient experience.

7. Results Posted in the Registry

• Aciclovir 200 mg: 69.3% (52/75) versus 97.3% (73/75) on control; risk difference -28.0 percentage points (95% CI -39.1 to -16.9), risk ratio 0.71 (0.61–0.83); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary outcome represent?

General explanation: a binary outcome classifies each participant into one of two categories, such as having or not having the event defined by the study. A group’s event count and denominator describe how often that classification occurred among participants included in the reported result. The registry posts 73 of 75 for famciclovir and 52 of 75 for aciclovir. The record does not define a separate analysis population or describe the handling of participants without an evaluable Day 5 result, so the exact relationship between randomized participants and the reported denominators is not clear.

What does the risk difference mean?

General explanation: a risk difference subtracts one group’s event proportion from the other’s. It is an absolute measure, expressed on the proportion scale. The posted comparison is aciclovir relative to famciclovir and gives an estimate of -0.28. The sign depends on the order of the groups: a negative value means the event proportion is lower in the first-named group under this contrast. This measure is often straightforward to interpret, but its meaning still depends on which event was counted and how it was defined.

How do relative risk and odds ratio differ?

General explanation: a relative risk divides the event proportion in one group by the event proportion in the comparison group. An odds ratio compares odds, where odds are the ratio of event to non-event counts. Both are relative measures, while the risk difference is absolute. When an event is frequent, an odds ratio may be farther from the no-effect value than a relative risk. The posted relative risk is 0.712 and the posted odds ratio is 0.062, both comparing aciclovir with famciclovir. These summaries do not represent separate endpoints or separate replications of the finding.

What does the p-value tell the reader?

General explanation: a p-value assesses how unusual data at least as incompatible with a null hypothesis would be if that hypothesis and the test’s assumptions held. It is not a measure of the probability that a treatment effect is real and does not describe the size of an effect. The registry reports an unadjusted p-value of <0.001. The test specification and assumptions are not reported in the registry record. As a result, the p-value can be quoted, but the specific calculation cannot be independently evaluated from the registry entries alone.

Why do the analysis details matter?

General explanation: an analysis plan identifies which participants are included, how outcomes are defined, how missing observations are handled, and which statistical methods are used. These choices can affect estimates and their uncertainty. Random allocation supports a comparison of assigned groups, but does not by itself resolve questions about loss to follow-up, deviations from assigned regimens, or outcome assessment. None of those details is described sufficiently in the registry record to establish the analysis population or the approach used.

For binary outcomes, the precision of a group comparison depends in part on the number of observations and the variability of the event counts. A confidence interval reflects uncertainty in an estimate under its method and assumptions. Wider intervals indicate less precision; narrower intervals indicate greater precision, without guaranteeing that the estimate is unbiased or that the endpoint is clinically comprehensive. The posted intervals are numerical summaries, but the registry does not identify the confidence level or construction method.

The trial is marked randomized and open-label. Randomization can balance measured and unmeasured characteristics on average across repeated allocations, but it does not guarantee exact balance in a particular trial. Open-label status means masking was not used according to the record. General methodological concern: awareness of assignment may influence care, reporting, or assessment, especially when an outcome requires judgment. The record does not describe whether the endpoint was assessed using an objective procedure or by blinded assessors, so the practical effect of the open-label design is not known.

Finally, statistical association in a trial result is not a complete account of clinical meaning. The posted endpoint count, contrast, and p-value describe the registered outcome at its stated time point. The endpoint’s operational definition, the treatment assignment process, and the handling of incomplete records are necessary context for judging the strength and scope of the inference. Those details are not reported in the registry record, so interpretation should remain tied to the posted comparison and avoid extending it to unmeasured outcomes.

10. Confidence Intervals and Precision

The risk-difference estimate for aciclovir relative to famciclovir is -0.28, with a reported interval from -0.391 to -0.170. The relative-risk estimate is 0.712, with an interval from 0.61 to 0.832. The odds-ratio estimate is 0.062, with an interval from 0.014 to 0.274. These intervals show a range of values compatible with the respective estimates under the methods used to construct them; they are not a range of individual participant outcomes.

General explanation: a confidence interval conveys statistical uncertainty around an estimate, conditional on the data and method. A narrower interval indicates greater precision than a wider one, while neither width nor location alone establishes that the method is appropriate or that the outcome has been measured without bias. For a risk difference, zero is the value corresponding to no difference; for relative risk and odds ratio, one is the value corresponding to no relative contrast. The posted intervals exclude those respective reference values.

The registry does not report the confidence level, the calculation method, or whether the intervals were prespecified. It also does not report an adjusted estimate. The precision should therefore be interpreted as reported, without assuming a particular confidence level or statistical model. The interval around the risk difference is the most direct expression of the absolute contrast; the relative measures express the comparison on different scales.

Uncertainty in these estimates is not the only limitation on interpretation. The result depends on the definition and assessment of the Day 5 endpoint, and information about missing observations and analysis populations is not reported in the registry record. An interval cannot account for biases caused by unreported outcome procedures or incomplete follow-up. Thus, the reported precision characterizes statistical uncertainty under the calculation, not every source of uncertainty about the result’s meaning or generalizability.

11. 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 table and curve are planning illustrations based on the observed effect, not a report of the trial’s original design calculation. The listed figures are participants per arm, not total events. The stated planning 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 a stated fraction of the observed effect.

For planning for 100% of the observed effect, The table shows 27 participants per arm for 80% power and 36 participants per arm for 90% power. For planning for 75% of the observed effect, it lists 40 participants per arm for 80% power and 53 participants per arm for 90% power. For planning for 50% of the observed effect, it lists 69 participants per arm for 80% power and 92 participants per arm for 90% power.

In plain terms, the 80% power column gives the planned participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions; the 90% column gives the planned participants per arm for a higher target chance under those assumptions. Smaller effects need more participants to detect than larger effects, which is reflected by the increasing figures as the assumed fraction of the observed effect declines.

These are planning calculations and are not observed power. The trial’s own original sample-size assumptions and justification are not reported in the registry record, so the illustrations should not be read as evidence about how the study was designed or whether its original target was met.

12. 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 = 0.973; treatment proportion p₁ = 0.693; average p̄ = 0.833.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5270 = 1.0330.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4884 = 0.4111.
4. n = (1.0330 + 0.4111)² / (-0.2800)² = 26.6, rounded up to 27 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 <- 0.973333333333333                          # control proportion
p1 <- 0.693333333333333                          # 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(1281007)
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 = 27 (80% power), 36 (90% power)
 75% of observed effect: n per arm = 40 (80% power), 53 (90% power)
 50% of observed effect: n per arm = 69 (80% power), 92 (90% power)
power.prop.test: 26.6 
Simulated power at n = 27 per arm: 0.881 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the trial had multiple primary hypotheses, whether any multiplicity adjustment was planned, or how such an adjustment would have been applied. There is one posted primary outcome and one posted secondary outcome, concerning adverse-event occurrence. The record lists two outcome measures, but does not provide a complete statistical analysis plan or explain whether there were additional comparisons, subgroups, or repeated assessments.

General explanation: multiplicity arises when several hypotheses or outcomes are tested. As the number of tests increases, the chance of at least one apparently notable result can increase if no adjustment or other control is used. A prespecified plan helps readers distinguish the main confirmatory question from additional analyses. Because the registry does not report such a plan, it is not possible to determine whether the posted p-value was selected from multiple analyses or whether any multiplicity strategy was used.

The registry record also does not report the analysis population, the handling of missing Day 5 observations, or whether the primary analysis followed the randomized assignment regardless of treatment received. General explanation: these decisions matter because excluding participants or handling missing outcomes differently can change the estimate and its uncertainty. The posted denominators are 75 in each arm, but the record does not explain whether these denominators represent all randomized participants, participants with observed outcomes, or another defined set.

No imputation method, sensitivity analysis, or protocol-deviation analysis is reported in the registry record. The record also does not describe interim analyses or stopping rules. These absences do not show that such methods were or were not used; they mean the registry information does not establish them. As a result, the reported estimate and unadjusted p-value should be interpreted without assuming a particular approach to missingness, multiplicity, or analysis populations.

14. Safety Results

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

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry reports zero serious adverse events among 75 participants at risk in the famciclovir group and zero among 75 at risk in the aciclovir group. It lists no serious adverse-event terms. Death counts are not reported in the registry record. For other adverse events, the posted counts are 10 among 75 at risk with famciclovir and 12 among 75 at risk with aciclovir.

These are event counts as posted, not a complete description of event severity, timing, duration, or relationship to treatment. The registry does not report the definition or collection procedures for adverse events, or details about follow-up and the analysis population. Zero reported serious events does not establish that serious events could not occur; it describes the registry’s posted count for this trial.

The other-adverse-event counts should not be treated as a formal comparison of safety without information about event definitions, ascertainment, and analysis. The record supplies no inferential comparison for these counts. The figures describe reported events in the trial and do not establish comparative safety beyond those observations.

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

The posted results show a difference between the recorded Day 5 endpoint counts in the two randomized groups: 73 of 75 participants in the famciclovir arm and 52 of 75 in the aciclovir arm. The registry’s risk-difference estimate for aciclovir relative to famciclovir is -0.28, and its unadjusted p-value is <0.001. The relative risk and odds ratio are also reported in the same comparison direction. These figures describe the endpoint as registered and analyzed in the posted result.

They do not, on their own, establish the clinical importance of that endpoint or explain what a “non-herpes manifestation” signifies for an individual participant. The symptom list is reported, but the endpoint’s operational definition and classification rules are not. Nor do the results establish effects on outcomes that were not measured or posted, on longer-term disease course, or on other patient experiences.

The trial is randomized, which is relevant to comparing assigned groups, but it is open-label and the registry does not report allocation procedures, assessor masking, or a full analysis plan. The reported contrast should not be interpreted as free from all potential bias. The registry also does not explain missing-data handling or define the analysis population, limiting assessment of whether the posted denominators capture all randomized participants.

The safety results are limited to the listed adverse-event counts. The record reports zero serious adverse events in each group, other-event counts of 10 and 12, and does not report death counts. These data are not enough to characterize every aspect of safety or to establish a comparative safety profile.

Overall, the posted data support a numerical difference in the registered Day 5 endpoint between the groups. The estimate and interval convey the size and statistical uncertainty of that comparison, subject to the record’s unreported methods and endpoint details. They should not be converted into treatment advice or a claim about outcomes beyond those actually reported.

16. Why This Trial Matters Statistically

This trial illustrates why a statistical result needs to be read together with its outcome definition. The registry describes a binary Day 5 endpoint and lists specific skin symptoms, but the phrase “non-herpes manifestation” is not operationally clarified. A numerical contrast can be calculated and reported precisely while the clinical meaning of the classification remains uncertain to readers.

It also shows the value of distinguishing absolute and relative measures. The risk difference of -0.28 gives the aciclovir-versus-famciclovir comparison on an absolute scale, while the relative risk and odds ratio express it on relative scales. Since these measures answer related but distinct questions, a reader should attend to the stated comparison direction and avoid treating one measure as a substitute for all others.

The randomized, open-label design provides useful context for interpreting group comparisons. Randomization is a design feature intended to support comparison, whereas lack of masking leaves possible routes for awareness of treatment assignment to affect treatment, reporting, or assessment. The registry does not say how the endpoint was assessed, so this issue cannot be resolved from the posted record.

Finally, precision and transparency are separate concerns. The record reports intervals and a p-value, but not the confidence level, interval method, analysis population, missing-data strategy, or complete statistical plan. Such omissions do not invalidate the numerical findings, but they limit independent appraisal of how the findings were produced and what assumptions underlie them. The planning illustrations also demonstrate that required sample size depends on the effect a future study aims to detect, rather than serving as a retrospective measure of this trial’s success.

17. 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 limitations specific to this trial follow from what the registry does and does not describe. The primary endpoint’s title refers to a non-herpes manifestation, while its description lists erythema, papule, vesicle, ulcer, crust, or healed skin. The registry does not specify the classification rule, how these symptoms relate to the endpoint label, or whether an evaluator used a standardized assessment procedure.

The study is marked as having no masking. The record does not report whether the primary outcome assessor was independent or unaware of assignment. Because the outcome depends on assessment of symptoms or skin findings, the absence of this information leaves uncertainty about the potential influence of open-label conduct.

The registry does not describe eligibility criteria beyond patients with active recurrent genital herpes, the randomization procedure, allocation concealment, the analysis population, or handling of missing outcomes and protocol deviations. It also does not give the primary analysis method, confidence level, or interval-construction method. These omissions constrain independent evaluation of the posted risk difference and intervals.

Safety information is limited to the posted serious and other adverse-event counts. Serious-event definitions, collection procedures, follow-up details, and death counts are not reported in the registry record. The registry’s planning illustrations are based on the observed effect and do not provide the original sample-size justification. These limitations concern reporting and interpretability; they do not establish that unreported procedures or analyses were absent from the conduct of the study.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy of Oral Famciclovir 125mg Comparing to Aciclovir 200 mg Treatment in Patients With Active Recurrent Genital Herpes — NCT01281007.
• Registry record last updated 2021-04-21; status last verified 2015-07.
• Results first posted 2015-07-07.
• 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.

21. Record Summary

NCT01281007 is a completed, randomized, open-label, parallel-group Phase 3 study comparing famciclovir 125 mg with aciclovir 200 mg in patients with active recurrent genital herpes. The registry lists enrollment of 150, a study start of 2012-07, and primary completion of 2015-01. The primary outcome is the number of subjects with a non-herpes manifestation at Day 5.

The posted counts are 73 of 75 with famciclovir and 52 of 75 with aciclovir. For aciclovir relative to famciclovir, the reported risk difference is -0.28, with an interval from -0.391 to -0.170, and the unadjusted p-value is <0.001. The record also reports relative-risk and odds-ratio estimates. Safety postings include zero serious adverse events in each arm and other-adverse-event counts of 10 and 12. Important details about endpoint classification, analysis populations, missing data, and statistical methods are not reported in the registry record.